Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Active Ulcerative Colitis
- Conditions
- Ulcerative Colitis
- Interventions
- Biological: adalimumabBiological: placebo
- Registration Number
- NCT00408629
- Lead Sponsor
- Abbott
- Brief Summary
This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of the human anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (ADA) in patients with moderately to severely active ulcerative colitis (UC).
- Detailed Description
This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of adalimumab (ADA) in patients with moderately to severely active ulcerative colitis (UC).
The duration of the study was up to 65 weeks, including a Screening Period of up to 3 weeks, a double-blind (DB) placebo-controlled treatment period of up to 52 weeks, and a 70 day follow-up phone call for participants who prematurely discontinued or who did not enroll in the extension study NCT# 00573794 (M10-223).
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 flexible sigmoidoscopy with biopsy, were to be enrolled at approximately 120 sites worldwide. Planned enrollment was 500 participants.
Participants were to be stratified by prior exposure to infliximab and/or other anti-TNF agents, and randomized in a 1:1 ratio to receive ADA or placebo by subcutaneous injection. Participants assigned to the ADA treatment arm were to receive an induction dose of 160 mg at Week 0 and 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4. Participants assigned to the placebo treatment arm were to receive matching placebo during the same period of time. At or after Week 10, participants who met the criteria for inadequate response could be switched to open-label (OL) ADA 40 mg eow beginning at Week 12. Inadequate response was defined as:
* Partial Mayo score greater than or equal to Baseline score on 2 consecutive visits at least 14 days apart (for participants with a partial Mayo score of 4 to 7 at Baseline).
* Partial Mayo score greater than or equal to 7 on 2 consecutive visits at least 14 days apart (for participants with a partial Mayo score of 8 or 9 at Baseline).
Participants who demonstrated inadequate response at 2 consecutive visits at least 14 days apart while on OL administration ADA 40 mg eow were permitted to dose escalate to ADA 40 mg weekly (ew). Participants with persistent inadequate response while on ADA 40 mg ew may have been discontinued from the study at the Investigator's discretion. Upon completion of the study, participants had the option to enroll into the OL extension Study M10-223 in which they could receive ADA treatment.
Efficacy and safety measurements were performed throughout the study. A follow-up phone call was made 70 days after the last dose of study drug to obtain information on any ongoing or new adverse events (AEs) for all participants who terminated early or who did not enroll in the OL extension study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 518
-
Participants >=18 years of age and in good health (Investigator discretion) with a recent stable medical history
-
Diagnosis of UC for greater than 90 days prior to Baseline
-
Diagnosis of active UC 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 >= 20 mg/day or equivalent) for at least 14 days prior to Baseline or maintenance, corticosteroid dose (prednisone < 20 mg/day or equivalent) for at least 40 days prior to Baseline
and/or
- At least a 90 day course of azathioprine (AZA) or 6-mercaptopurine (6-MP) prior to Baseline, with a dose of AZA >= 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 must 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 (AZA or 6-MP) during the past 5 years and in the judgment of the Investigator have failed to respond to, or could not tolerate, their treatment.
-
Participants may have been included if they had previously used an anti-tumor necrosis factor (TNF) agent (except ADA) and discontinued its use due to a loss of response or intolerance to the agent.
-
Had to be able to self-administer or had caregiver who could reliably administer subcutaneous (SC) injections.
-
Had to be able and willing to give written informed consent and to comply with the requirements of the 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 the 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, 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 must have been negative.
-
Judged to be in generally good health as determined by the Investigator
- History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC, or planned bowel surgery.
- Received previous treatment with ADA or previous participation in an ADA clinical study.
- Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days of Baseline.
- Received intravenous (IV) corticosteroids within 14 days of Screening or during the Screening Period.
- Received therapeutic enema or suppository, other than required for endoscopy, within 14 days of the Screening endoscopy and during the remainder of the Screening Period.
- Current diagnosis of fulminant colitis and/or toxic megacolon.
- Disease limited to the rectum (ulcerative proctitis).
- Current diagnosis of indeterminate colitis.
- Current diagnosis and/or history of Crohns disease (CD).
- Currently receiving total parenteral nutrition.
- Used aminosalicylates for < 90 days before Baseline or not on a stable dose for at least 28 days before Baseline or discontinued use within 28 days of Baseline.
- Positive Clostridium difficile stool assay.
- Previously used infliximab or any anti-TNF agent within 56 days of Baseline.
- Previously used infliximab or any anti-TNF agent without clinical response at any time ("primary non-responder") unless subject experienced a treatment-limiting reaction.
- Infections requiring treatment with IV antibiotics, antivirals, or antifungals within 30 days of Baseline or oral antibiotics, antivirals, or antifungals within 14 days of 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, subject was not to be enrolled in the study.
- History of listeria, histoplasmosis, chronic or active hepatitis B infection, human immunodeficiency virus (HIV), immunodeficiency syndrome, central nervous system demyelinating disease, or untreated tuberculosis (TB).
- Female subject who was pregnant or breast-feeding or considering becoming pregnant during the study (there should be at least 150 days 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 (CHF), recent cerebrovascular accident, and any other condition, which in the opinion of the investigator, put the subject at risk by participation in the protocol.
- Received any investigational agent within 30 days or 5 half lives prior to Baseline (whichever was longer).
- History of clinically significant drug or alcohol abuse during the past year.
- Known hypersensitivity to the excipients of ADA as stated in the label.
- Any prior exposure to Tysabri® (natalizumab), or Orencia® (abatacept) or any other biological therapy [other than Kineret® (anakinra) and anti-TNF agents].
- Currently taking both budesonide and prednisone (or equivalent) simultaneously.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description adalimumab group adalimumab - placebo group placebo -
- Primary Outcome Measures
Name Time Method Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 8 Week 8 Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 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 (SFS), Rectal Bleeding Subscore (RBS), Endoscopy Subscore, and Physician's Global Assessment Subscore (PGA), each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 52 Week 52 Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
- Secondary Outcome Measures
Name Time Method Proportion of Participants Who Achieved Sustained Clinical Remission Per Mayo Score at Both Week 8 and Week 52 Week 8, Week 52 Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 8 Week 8 Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in rectal bleeding subscore (RBS) of at least 1 point from Baseline or an absolute RBS 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 52 Week 52 Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in RBS of at least 1 point from Baseline or an absolute RBS 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants Who Achieved Sustained Clinical Response Per Mayo Score at Both Week 8 and Week 52 Week 8, Week 52 Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in RBS of at least 1 point from Baseline or an absolute RBS 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants Who Achieved Mucosal Healing at Week 8 Week 8 Mucosal healing is defined as an 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 Who Achieved Mucosal Healing at Week 52 Week 52 Mucosal healing is defined as an 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 Who Achieved Sustained Mucosal Healing at Both Week 8 and Week 52 Week 8, Week 52 Mucosal healing is defined as an 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 Who Discontinued Corticosteroid Use Before Week 52 and Achieved Clinical Remission Per Mayo Score at Week 52 Baseline to Week 52 Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8 Week 8 The PGA includes the 3 other subscores (SFS, RBS, and Endoscopy), the participant's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the participant'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 (a Score of 0 or 1) at Week 8 Week 8 SFS 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. The participant served as his/her own control.Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8 Week 8 RBS 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 passedProportion of Participants Who Discontinued Corticosteroid Use for At Least 90 Days and Achieved Clinical Remission Per Mayo Score at Week 52 Baseline to Week 52 Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Participants Who Discontinued Corticosteroid Use and Achieved Clinical Remission Per Mayo Score (Sustained) at Both Weeks 32 and 52 Week 32, Week 52 Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 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:
SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 52 Week 52 Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) was defined as at least 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 questions 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 Inflammatory Bowel Disease Questionnaire Responders at Week 8 Week 8 Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) was defined as at least 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 questions 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).
Trial Locations
- Locations (108)
Site Ref # / Investigator 3739
🇺🇸Atlanta, Georgia, United States
Site Ref # / Investigator 5197
🇳🇴Oslo, Norway
Site Ref # / Investigator 6297
🇳🇴Oslo, Norway
Site Ref # / Investigator 5194
🇳🇴Tromso, Norway
Site Ref # / Investigator 5242
🇵🇱Lodz, Poland
Site Ref # / Investigator 5266
🇵🇱Warsaw, Poland
Site Ref # / Investigator 5265
🇵🇱Warsaw, Poland
Site Ref # / Investigator 15263
🇵🇱Wroclaw, Poland
Site Ref # / Investigator 7473
🇵🇹Lisbon, Portugal
Site Ref # / Investigator 6853
🇦🇷Buenos Aires, Argentina
Site Ref # / Investigator 6225
🇧🇪Brussels, Belgium
Site Ref # / Investigator 3764
🇨🇦Montreal, Quebec, Canada
Site Ref # / Investigator 6307
🇨🇿Hradec Kravlove 12, Czech Republic
Site Ref # / Investigator 6606
🇨🇿Olomouc, Czech Republic
Site Ref # / Investigator 7481
🇨🇿Prague 4, Czech Republic
Site Ref # / Investigator 7479
🇨🇿Prague 5, Czech Republic
Site Ref # / Investigator 5025
🇭🇺Budapest, Hungary
Site Ref # / Investigator 5036
🇭🇺Miskolc, Hungary
Site Ref # / Investigator 10623
🇮🇱Petah Tikva, Israel
Site Ref # / Investigator 15361
🇮🇱Tel Aviv, Israel
Site Ref # / Investigator 9561
🇳🇴Gjovik, Norway
Site Ref # / Investigator 7453
🇺🇸Topeka, Kansas, United States
Site Ref # / Investigator 10704
🇦🇺Fremantle, Western Australia, Australia
Site Ref # / Investigator 5397
🇺🇸Moline, Illinois, United States
Site Ref # / Investigator 3753
🇺🇸Wheat Ridge, Colorado, United States
Site Ref # / Investigator 5106
🇺🇸Jacksonville, Florida, United States
Site Ref # / Investigator 3765
🇺🇸Sayre, Pennsylvania, United States
Site Ref # / Investigator 11601
🇺🇸Naples, Florida, United States
Site Ref # / Investigator 6846
🇺🇸Sarasota, Florida, United States
Site Ref # / Investigator 3752
🇺🇸Charlotte, North Carolina, United States
Site Ref # / Investigator 5394
🇺🇸Anaheim, California, United States
Site Ref # / Investigator 12903
🇺🇸Gainesville, Florida, United States
Site Ref # / Investigator 3742
🇺🇸Winter Park, Florida, United States
Site Ref # / Investigator 3750
🇺🇸Spokane, Washington, United States
Site Ref # / Investigator 3758
🇺🇸Jacksonville, North Carolina, United States
Site Ref # / Investigator 3769
🇨🇦Hamilton, Ontario, Canada
Site Ref # / Investigator 3760
🇺🇸Zephyrhills, Florida, United States
Site Ref # / Investigator 3740
🇺🇸Tulsa, Oklahoma, United States
Site Ref # / Investigator 10706
🇦🇺Bedford Park, South Australia, Australia
Site Ref # / Investigator 5247
🇩🇪Regensburg, Germany
Site Ref # / Investigator 13722
🇦🇺Garran, Australian Capital Territory, Australia
Site Ref # / Investigator 5398
🇺🇸Ogden, Utah, United States
Site Ref # / Investigator 14661
🇩🇪Munich, Germany
Site Ref # / Investigator 13723
🇦🇺Herston, Queensland, Australia
Site Ref # / Investigator 4987
🇭🇺Miskoic, Hungary
Site Ref # / Investigator 7476
🇫🇷Lille Cedex, France
Site Ref # / Investigator 7475
🇫🇷Pessac Cedex, France
Site Ref # / Investigator 9069
🇩🇪Hamburg, Germany
Site Ref # / Investigator 3741
🇺🇸Columbia, South Carolina, United States
Site Ref # / Investigator 14642
🇩🇪Magdeburg, Germany
Site Ref # / Investigator 6483
🇩🇰Hvidovre, Denmark
Site Ref # / Investigator 7477
🇩🇰Odense C, Denmark
Site Ref # / Investigator 14761
🇩🇪Muenster, Germany
Site Ref # / Investigator 7474
🇫🇷Toulouse, France
Site Ref # / Investigator 13482
🇳🇿Hamilton, New Zealand
Site Ref # / Investigator 3761
🇺🇸West Bend, Wisconsin, United States
Site Ref # / Investigator 16141
🇦🇺Bankstown, New South Wales, Australia
Site Ref # / Investigator 13556
🇨🇦Sudbury, Ontario, Canada
Site Ref # / Investigator 3736
🇨🇦Toronto, Ontario, Canada
Site Ref # / Investigator 6231
🇫🇷Clichy, France
Site Ref # / Investigator 9801
🇩🇪Munich, Germany
Site Ref # / Investigator 5212
🇪🇸Madrid, Spain
Site Ref # / Investigator 9067
🇩🇪Minden, Germany
Site Ref # / Investigator 13301
🇳🇿Auckland, New Zealand
Site Ref # / Investigator 13181
🇳🇿Auckland, New Zealand
Site Ref # / Investigator 5193
🇳🇴Trondheim, Norway
Site Ref # / Investigator 5264
🇵🇹Faro, Portugal
Site Ref # / Investigator 5263
🇵🇹Lisbon, Portugal
Site Ref # / Investigator 10222
🇨🇭Bern, Switzerland
Site Ref # / Investigator 5211
🇪🇸Barcelona, Spain
Site Ref # / Investigator 10221
🇨🇭Basel, Switzerland
Site Ref # / Investigator 9162
🇨🇭Zurich, Switzerland
Site Ref # / Investigator 3745
🇺🇸Cincinnati, Ohio, United States
Site Ref # / Investigator 7709
🇺🇸Oklahoma City, Oklahoma, United States
Site Ref # / Investigator 3744
🇺🇸Rochester, Minnesota, United States
Site Ref # / Investigator 6077
🇺🇸Nashville, Tennessee, United States
Site Ref # / Investigator 5107
🇺🇸Nashville, Tennessee, United States
Site Ref # / Investigator 3743
🇺🇸Nashville, Tennessee, United States
Site Ref # / Investigator 3747
🇺🇸Hollywood, Florida, United States
Site Ref # / Investigator 7658
🇺🇸Macon, Georgia, United States
Site Ref # / Investigator 3759
🇺🇸Annapolis, Maryland, United States
Site Ref # / Investigator 3756
🇺🇸Great Neck, New York, United States
Site Ref # / Investigator 7472
🇺🇸Troy, Michigan, United States
Site Ref # / Investigator 9802
🇦🇹Vienna, Austria
Site Ref # / Investigator 3737
🇺🇸Germantown, Tennessee, United States
Site Ref # / Investigator 8064
🇺🇸Spokane, Washington, United States
Site Ref # / Investigator 6079
🇧🇪Ghent, Belgium
Site Ref # / Investigator 9002
🇦🇺Malvern, Victoria, Australia
Site Ref # / Investigator 5256
🇧🇪Bonheiden, Belgium
Site Ref # / Investigator 5253
🇧🇪Brussels, Belgium
Site Ref # / Investigator 6078
🇧🇪Leuven, Belgium
Site Ref # / Investigator 15321
🇩🇪Hamburg, Germany
Site Ref # / Investigator 3768
🇨🇦Montreal, Quebec, Canada
Site Ref # / Investigator 3770
🇨🇦Quebec City, Quebec, Canada
Site Ref # / Investigator 14104
🇭🇺Gyula, Hungary
Site Ref # / Investigator 13148
🇳🇿Christchurch, New Zealand
Site Ref # / Investigator 10625
🇭🇺Debrecen, Hungary
Site Ref # / Investigator 12744
🇮🇱Kfar Saba, Israel
Site Ref # / Investigator 6088
🇺🇸St. Louis, Missouri, United States
Site Ref # / Investigator 3771
🇨🇦Montreal, Quebec, Canada
Site Ref # / Investigator 7021
🇨🇿Ceske Budejovice, Czech Republic
Site Ref # / Investigator 3766
🇨🇦Victoria, British Columbia, Canada
Site Ref # / Investigator 7485
🇭🇺Budapest, Hungary
Site Ref # / Investigator 3754
🇺🇸Hamden, Connecticut, United States
Site Ref # / Investigator 3762
🇺🇸Annapolis, Maryland, United States
Site Ref # / Investigator 3738
🇺🇸Lutherville, Maryland, United States
Site Ref # / Investigator 14882
🇦🇺Box Hill, Victoria, Australia
Site Ref # / Investigator 10423
🇨🇦Kelowna, British Columbia, Canada