Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Acute Ulcerative Colitis

Phase 3

Completed

Conditions: Ulcerative Colitis

Interventions: Biological: adalimumab
Biological: placebo

Registration Number: NCT00385736

Lead Sponsor: Abbott

Brief Summary: The objective of this study is to assess the efficacy and safety of adalimumab for the induction of clinical remission in subjects with moderately to severely active ulcerative colitis.

Detailed Description: This was a Phase 3, multicenter, randomized, double-blind (DB), placebo-controlled trial designed to evaluate the efficacy and safety of the human anti-TNF monoclonal antibody adalimumab for the induction of clinical remission in participants with moderately to severely active ulcerative colitis (UC).

Adult participants with moderate to severe UC (Mayo score of 6 to 12 points with endoscopy subscore of 2 to 3 points), confirmed by colonoscopy with biopsy or by flexible sigmoidoscopy with biopsy, were enrolled at 80 sites worldwide. The study enrolled 576 participants, including 186 participants under the original protocol and protocol Amendments 1 and 2, and 390 participants under protocol Amendments 3 and 4.

Participants enrolled in the study prior to Amendment 3 were randomized in a 1:1 ratio to receive adalimumab or placebo during the 12-week DB induction period. Participants received 4 injections of adalimumab 40 mg (160 mg) or 4 injections of placebo at Baseline (Week 0), followed by 2 injections of adalimumab 40 mg (80 mg) or 2 injections of placebo at Week 2, followed by 1 injection of adalimumab 40 mg or placebo at Weeks 4 and 6. At Week 8, participants randomized to placebo received 4 injections of adalimumab 40 mg (160 mg) followed by 2 injections of adalimumab 40 mg (80 mg) at Week 10. Participants randomized to adalimumab received 3 injections of placebo and 1 injection of adalimumab 40 mg at Week 8 and 1 injection of placebo and 1 injection of adalimumab 40 mg at Week 10. All participants continued to receive 1 injection of open-label (OL) adalimumab 40 mg every other week beginning at Week 12 up to Week 52 (or the early termination visit). Starting at Week 14, participants who had inadequate responses to treatment (as defined using partial Mayo scores) were permitted to dose escalate to adalimumab 40 mg weekly. Participants with persistent inadequate response while on weekly treatment could be discontinued from the study at the discretion of the investigator.

In August 2007, the study design was amended to incorporate an additional adalimumab induction dosing arm of 80/40 mg. Earlier that year, both 160/80-mg and 80/40-mg induction regimens had been approved in the EU as induction treatment for Crohn's disease. The adalimumab induction dosing regimen of 80/40 mg was therefore included so that both of these approved induction regimens would be evaluated for the induction of remission of UC.

Participants enrolled in the study after Amendment 3 were randomized in a 1:1:1 ratio to receive adalimumab (1 of 2 regimens) or placebo during the 8-week DB induction period. Participants received DB therapy from Baseline until Week 8 and OL therapy from Week 8 until the end of the study. In the first adalimumab dosing arm (adalimumab 80/40), participants received 2 injections of adalimumab 40 mg (80 mg) and 2 injections of placebo at Baseline followed by 1 injection of adalimumab 40 mg and 1 injection of placebo at Week 2, and 1 injection of adalimumab 40 mg every other week thereafter. In the second adalimumab DB induction dosing arm (adalimumab 160/80), participants received 4 injections of adalimumab 40 mg (160 mg) at Baseline followed by 2 injections of adalimumab 40 mg (80 mg) at Week 2, and 1 injection of adalimumab 40 mg every other week thereafter. Participants randomized to placebo received 4 injections of placebo at Baseline followed by 2 injections of placebo at Week 2, and 1 injection of placebo at Weeks 4 and 6. Beginning at Week 8, but after the Week 8 study assessments had been completed, all participants received 1 injection of OL adalimumab 40 mg every other week until Week 52 or early termination. Starting at Week 12, participants who had inadequate responses to treatment (as defined using partial Mayo scores) were permitted to dose escalate to adalimumab 40 mg weekly. Participants with persistent inadequate response while on weekly treatment could be discontinued from the study at the discretion of the investigator.

For the analysis of efficacy parameters during the DB Period through Week 8, only participants randomized under Protocol Amendment 3 or later were considered ("Efficacy Analysis Set - Induction" in the participant flow). For the analysis of efficacy parameters during the OL Period through Week 52, all randomized participants (under any version of the protocol) who received at least 1 dose of study drug were considered ("Efficacy Analysis Set - Maintenance" in the participant flow). For the analysis of safety parameters, all participants who received at least 1 dose of study drug were considered ("Safety Analysis Set" in the participant flow).

Twelve ranked secondary variables during the DB Period through Week 8 were to be tested in a hierarchical order to account for multiple testing. These variables are identified as "Ranked Secondary Endpoints" in the results section below. Additionally, non-ranked secondary variables during the OL Period through Week 52 were tested and are presented after the ranked secondary endpoints in the results section below.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 576

Inclusion Criteria

Male and female participants >= 18 years of age
Diagnosis of ulcerative colitis for greater than 90 days prior to Baseline
Diagnosis of active ulcerative colitis confirmed by colonoscopy with biopsy or flexible sigmoidoscopy with biopsy during the Screening Period, with exclusion of infection
Active UC with a Mayo score of 6 to 12 points and endoscopy subscore of 2 to 3 points, despite concurrent treatment with at least 1 of the following (oral corticosteroids or immunosuppressants or both as defined below):
- Stable oral corticosteroid dose (prednisone dose of >= 20 mg/day or equivalent) for at least 14 days prior to Baseline or stable oral corticosteroid dose (prednisone of < 20 mg/day) for at least 40 days prior to Baseline.
and/or
- At least a consecutive 90 day course of azathioprine or 6-mercaptopurine (6 MP) prior to Baseline, with a dose of azathioprine >= 1.5 mg/kg/day or 6 MP >= 1 mg/kg/day (rounded to the nearest available tablet formulation), or a dose that is the highest tolerated by the participant (e.g., due to leukopenia, elevated liver enzymes, nausea) during that time. Participant was to be on a stable dose for at least 28 days prior to Baseline.
Concurrent therapy was not required for participants who were previously treated with corticosteroids or immunosuppressants (azathioprine or 6-MP) during the previous 5 years and, in the judgment of the investigator, have failed to respond to or could not tolerate their treatment.
Had to be able to self-administer or has caregiver who can reliably administer subcutaneous injections.
Had to be able and willing to give written informed consent and to comply with the requirements of this study protocol.
Female had to be either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or of childbearing potential and practicing an approved method of birth control throughout the study and for 150 days after last dose of study drug. Examples of approved methods of birth control included the following:
- Condoms, sponge, foams, jellies, diaphragm or intrauterine device
- Oral, parenteral or intravaginal contraceptives for 90 days prior to study drug administration
- A vasectomized partner
The results of the serum pregnancy test performed at the Screening Visit and urine pregnancy test performed at the Baseline Visit had to be negative.
Judged to be in generally good health as determined by the principal investigator

Exclusion Criteria

History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for ulcerative colitis or is planning bowel surgery.
Received infliximab or any other anti-TNF agent or any biological therapy in the past.
Received previous treatment with adalimumab or previous participation in an adalimumab clinical study.
Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
Received therapeutic enema or suppository, other than required for endoscopy, within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
Current diagnosis of fulminant colitis and/or toxic megacolon.
Participants with disease limited to the rectum (ulcerative proctitis).
Current diagnosis of indeterminate colitis.
Current diagnosis and/or history of Crohn's disease.
Currently receiving total parenteral nutrition.
Discontinued use of azathioprine or 6-MP within 28 days of Baseline.
Discontinued use of corticosteroid within 14 days of Baseline.
Participants using aminosalicylates for less than 90 days prior to Baseline, not on a stable dose for at least 28 days prior to Baseline, or discontinued use within 28 days of Baseline.
Participants with positive Clostridium difficile stool assay.
Infections requiring treatment with intravenous (IV) antibiotics, IV antivirals, or IV antifungals within 30 days prior to Baseline or oral antibiotics, oral antivirals, or oral antifungals within 14 days prior to Baseline.
History of malignancy other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix. If the Screening colonoscopy/flexible sigmoidoscopy showed evidence of dysplasia or a malignancy, the participant was not to be enrolled in the study.
History of listeria, histoplasmosis, chronic or active hepatitis B infection, human immunodeficiency virus, immunodeficiency syndrome, central nervous system demyelinating disease, or untreated tuberculosis (TB).
Female participants who was pregnant or breast-feeding or considering becoming pregnant during the study. There should be at least a 150-day period between the last dose of study drug and either conception or initiation of breast-feeding in women of childbearing potential.
Poorly controlled medical condition(s), such as uncontrolled diabetes, unstable ischemic heart disease, moderate to severe congestive heart failure, recent cerebrovascular accident and any other condition, which in the opinion of the investigator, would put the participant at risk by participation in the protocol.
Received any investigational agent within 30 days or 5 half lives prior to Baseline (whichever is longer).
History of clinically significant drug or alcohol abuse during the previous year.
Participants with known hypersensitivity to the excipients of adalimumab as stated in the label.
Participants with any prior exposure to Tysabri® (natalizumab).
Participants currently taking both budesonide and prednisone (or equivalent) simultaneously.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adalimumab 80/40	adalimumab	-
Adalimumab 160/80/40	adalimumab	-
Placebo	placebo	-

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Clinical Remission Per Mayo Score at Week 8	Week 8	Clinical remission per Mayo score is defined as a total Mayo score \<= 2 and no individual subscore \> 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).

Secondary Outcome Measures

Name	Time	Method
Ranked Secondary Endpoint #1: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 160/80/40 Versus Placebo).	Week 8	Clinical response per Mayo score is defined as a decrease in Mayo score of \>= 3 points and \>= 30% from Baseline, plus either a decrease in rectal bleeding subscore of \>= 1 point or an absolute rectal bleeding subscore of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Ranked Secondary Endpoint #2: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 160/80/40 Versus Placebo).	Week 8	Mucosal healing is defined as Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease (spontaneous bleeding, ulceration)
Ranked Secondary Endpoint #3: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).	Week 8	Rectal Bleeding Subscore ranges from 0-3 as follows: 0 = no blood seen, 1 = streaks of blood with stool less than half the time, 2 = obvious blood with stool most of the time, 3 = blood alone passed
Ranked Secondary Endpoint #5: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).	Week 8	Stool Frequency Subscore ranges from 0-3 as follows: 0 = Normal number of stools for this participant, 1 = 1-2 stools more than normal, 2 = 3-4 stools more than normal, 3 = 5 or more stools more than normal
Ranked Secondary Endpoint #4: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).	Week 8	The Physician's Global Assessment Subscore acknowledges the 3 other subscores (Stool Frequency, Rectal Bleeding, and Endoscopy), the subject's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the subject's performance status. Possible scores range from 0-3 as follows: 0 = Normal (other subscores are 0), 1 = Mild disease (other subscores are mostly 1), 2 = Moderate disease (other subscores are 1 to 2), 3 = Severe disease (other subscores are 2 to 3)
Ranked Secondary Endpoint #6: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 80/40 Versus Placebo).	Week 8	Clinical response per Mayo score is defined as a decrease in Mayo score of \>= 3 points and \>= 30% from Baseline, plus either a decrease in rectal bleeding subscore of \>= 1 point or an absolute rectal bleeding subscore of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Ranked Secondary Endpoint #7: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 80/40 Versus Placebo).	Week 8	Mucosal healing defined as Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease (spontaneous bleeding, ulceration)
Ranked Secondary Endpoint #8: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).	Week 8	Rectal Bleeding Subscore ranges from 0-3 as follows: 0 = no blood seen, 1 = streaks of blood with stool less than half the time, 2 = obvious blood with stool most of the time, 3 = blood alone passed
Ranked Secondary Endpoint #9: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).	Week 8	The Physician's Global Assessment Subscore acknowledges the 3 other subscores (Stool Frequency, Rectal Bleeding, and Endoscopy), the subject's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the subject's performance status. Possible scores range from 0-3 as follows: 0 = Normal (other subscores are 0), 1 = Mild disease (other subscores are mostly 1), 2 = Moderate disease (other subscores are 1 to 2), 3 = Severe disease (other subscores are 2 to 3)
Ranked Secondary Endpoint #10: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).	Week 8	Stool Frequency Subscore ranges from 0-3 as follows: 0 = Normal number of stools for this participant, 1 = 1-2 stools more than normal, 2 = 3-4 stools more than normal, 3 = 5 or more stools more than normal
Ranked Secondary Endpoint #11: Proportion of IBDQ Responders at Week 8 (Adalimumab 160/80/40 Versus Placebo).	Week 8	Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) defined as a \>= 16-point increase from Baseline in total IBDQ score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to each question within each domain range from 1 (significant impairment) to 7 (no impairment), with total score ranging from 32 (very poor) to 224 (perfect health-related quality of life).
Ranked Secondary Endpoint #12: Proportion of IBDQ Responders at Week 8 (Adalimumab 80/40 Versus Placebo).	Week 8	Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) defined as a \>= 16-point increase from Baseline in total IBDQ score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to each question within each domain range from 1 (significant impairment) to 7 (no impairment), with total score ranging from 32 (very poor) to 224 (perfect health-related quality of life).
Proportion of Participants With Clinical Remission Per Mayo Score at Week 52	Week 52	Clinical remission per Mayo score is defined as a total Mayo score \<= 2 and no individual subscore \> 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Proportion of Participants With Clinical Remission Per Partial Mayo Score at Week 52	Week 52	Clinical remission per partial Mayo score is defined as a partial Mayo score \<= 2 and no individual subscore \> 1. The partial Mayo score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Proportion of Participants With Clinical Response Per Mayo Score at Week 52	Week 52	Clinical response per Mayo score is defined as a decrease in Mayo score of \>= 3 points and \>= 30% from Baseline, plus either a decrease in rectal bleeding subscore of \>= 1 point or an absolute rectal bleeding subscore of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Proportion of Participants With Clinical Response Per Partial Mayo Score at Week 52	Week 52	Clinical response per partial Mayo score is defined as a decrease in partial Mayo score of \>= 2 points and \>= 30% from Baseline, plus either a decrease in rectal bleeding subscore of \>= 1 point or an absolute rectal bleeding subscore of 0 or 1. The partial Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).
Proportion of Participants With Mucosal Healing at Week 52	Week 52	Mucosal healing is defined as Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease (spontaneous bleeding, ulceration)
Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 52	Week 52	Rectal Bleeding Subscore ranges from 0-3 as follows: 0 = no blood seen, 1 = streaks of blood with stool less than half the time, 2 = obvious blood with stool most of the time, 3 = blood alone passed
Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 52	Week 52	The Physician's Global Assessment Subscore acknowledges the 3 other subscores (Stool Frequency, Rectal Bleeding, and Endoscopy), the subject's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the subject's performance status. Possible scores range from 0-3 as follows: 0 = Normal (other subscores are 0), 1 = Mild disease (other subscores are mostly 1), 2 = Moderate disease (other subscores are 1 to 2), 3 = Severe disease (other subscores are 2 to 3)
Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 52	Week 52	Stool Frequency Subscore ranges from 0-3 as follows: 0 = Normal number of stools for this participant, 1 = 1-2 stools more than normal, 2 = 3-4 stools more than normal, 3 = 5 or more stools more than normal
Proportion of Participants With Clinical Remission Per Mayo Score at Week 52 Among Participants Who Were Systemic Corticosteroid-free at Week 52	Week 52	Clinical remission per Mayo score is defined as a total Mayo score \<= 2 and no individual subscore \> 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, Endoscopy Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease).

Trial Locations

Locations (80): Site Ref # / Investigator 4937
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Vienna, Austria
Site Ref # / Investigator 7508
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Linz, Austria
Site Ref # / Investigator 3858
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Brno, Czech Republic
Site Ref # / Investigator 3856
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Olomouc, Czech Republic
Site Ref # / Investigator 3857
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Ostrava, Czech Republic
Site Ref # / Investigator 3849
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Gyor, Hungary
Site Ref # / Investigator 2392
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Ponce, Puerto Rico
Site Ref # / Investigator 3873
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Eindhoven, Netherlands
Site Ref # / Investigator 3875
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Leiden, Netherlands
Site Ref # / Investigator 3839
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Banska Bystrica, Slovakia
Site Ref # / Investigator 14521
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Trencin, Slovakia
Site Ref # / Investigator 13804
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Sopot, Poland
Site Ref # / Investigator 2231
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Atlanta, Georgia, United States
Site Ref # / Investigator 2498
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Chicago, Illinois, United States
Site Ref # / Investigator 3830
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Innsbruck, Austria
Site Ref # / Investigator 2080
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Birmingham, Alabama, United States
Site Ref # / Investigator 6224
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Hall, Austria
Site Ref # / Investigator 1971
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Boston, Massachusetts, United States
Site Ref # / Investigator 2232
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Raleigh, North Carolina, United States
Site Ref # / Investigator 5392
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San Diego, California, United States
Site Ref # / Investigator 2243
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Kansas City, Missouri, United States
Site Ref # / Investigator 2240
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Gainesville, Florida, United States
Site Ref # / Investigator 5390
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Orange, California, United States
Site Ref # / Investigator 2126
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Cleveland, Ohio, United States
Site Ref # / Investigator 3846
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Rome, Italy
Site Ref # / Investigator 2077
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Milwaukee, Wisconsin, United States
Site Ref # / Investigator 3834
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Jena, Germany
Site Ref # / Investigator 3832
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Berlin, Germany
Site Ref # / Investigator 3833
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Kiel, Germany
Site Ref # / Investigator 2247
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Mexico, Missouri, United States
Site Ref # / Investigator 2138
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Toronto, Ontario, Canada
Site Ref # / Investigator 8504
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Linkoping, Sweden
Site Ref # / Investigator 3861
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Bonheiden, Belgium
Site Ref # / Investigator 3848
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Milan, Italy
Site Ref # / Investigator 8503
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Gothenburg, Sweden
Site Ref # / Investigator 8502
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Lund, Sweden
Site Ref # / Investigator 13983
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Essen, Germany
Site Ref # / Investigator 3876
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Bologna, Italy
Site Ref # / Investigator 3845
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Palermo, Italy
Site Ref # / Investigator 6232
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Rome, Italy
Site Ref # / Investigator 6034
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Mobile, Alabama, United States
Site Ref # / Investigator 3897
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Munich, Germany
Site Ref # / Investigator 2246
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Rochester, Minnesota, United States
Site Ref # / Investigator 2241
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Charlotte, North Carolina, United States
Site Ref # / Investigator 2074
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Cincinnati, Ohio, United States
Site Ref # / Investigator 5100
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Fayetteville, Arkansas, United States
Site Ref # / Investigator 5393
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Atlanta, Georgia, United States
Site Ref # / Investigator 2230
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South Miami, Florida, United States
Site Ref # / Investigator 2078
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Chevy Chase, Maryland, United States
Site Ref # / Investigator 2238
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Silver Springs, Maryland, United States
Site Ref # / Investigator 11801
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Wilmington, North Carolina, United States
Site Ref # / Investigator 2072
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New York, New York, United States
Site Ref # / Investigator 2229
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Bellevue, Washington, United States
Site Ref # / Investigator 3829
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Salzburg, Austria
Site Ref # / Investigator 3854
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Prague 1, Czech Republic
Site Ref # / Investigator 2227
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Edmonton, Alberta, Canada
Site Ref # / Investigator 3842
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Nitra, Slovakia
Site Ref # / Investigator 3878
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Mainz, Germany
Site Ref # / Investigator 3840
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Trnava, Slovakia
Site Ref # / Investigator 2223
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Winnipeg, Manitoba, Canada
Site Ref # / Investigator 2245
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Bridgeport, Connecticut, United States
Site Ref # / Investigator 2236
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Cedar Knolls, New Jersey, United States
Site Ref # / Investigator 4936
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Graz, Austria
Site Ref # / Investigator 3831
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Vienna, Austria
Site Ref # / Investigator 3859
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Liege, Belgium
Site Ref # / Investigator 3862
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Roeselare, Belgium
Site Ref # / Investigator 2233
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Lincoln, Nebraska, United States
Site Ref # / Investigator 6090
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Germantown, Tennessee, United States
Site Ref # / Investigator 2076
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Nashville, Tennessee, United States
Site Ref # / Investigator 2224
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Calgary, Alberta, Canada
Site Ref # / Investigator 3855
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Prague 7, Czech Republic
Site Ref # / Investigator 8061
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Lodz, Poland
Site Ref # / Investigator 8055
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Warsaw, Poland
Site Ref # / Investigator 2393
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San Juan, Puerto Rico
Site Ref # / Investigator 3838
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Bratislava, Slovakia
Site Ref # / Investigator 3841
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Bratislava, Slovakia
Site Ref # / Investigator 14721
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Presov, Slovakia
Site Ref # / Investigator 3852
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Budapest, Hungary
Site Ref # / Investigator 3850
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Budapest, Hungary
Site Ref # / Investigator 2226
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Vancouver, British Columbia, Canada