Multicenter, Phase I, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, Immunogenicity, Pharmacokinetics, Pharmacodynamics and Efficacy of Multiple Ascending Doses of Subcutaneous MSB0010841 (Anti-IL17A/F Nanobody) in Male and Female Subjects With Moderate to Severe Psoriasis
Overview
- Phase
- Phase 1
- Intervention
- MSB0010841
- Conditions
- Psoriasis
- Sponsor
- Merck KGaA, Darmstadt, Germany
- Enrollment
- 41
- Locations
- 1
- Primary Endpoint
- MSB0010841 Serum Concentration Over Time After First Dose
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
This is a multicenter, Phase 1, randomized, double-blind, placebo-controlled trial in subjects with moderate to severe psoriasis to assess the safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of multiple subcutaneous ascending doses of MSB0010841 (Anti-interleukin-17A/F [Anti-IL-17A/F] Nanobody).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Chronic plaque psoriasis for at least 6 months before screening
- •Greater than or equal to (\>=) 10% of BSA with plaques
- •Psoriasis Area and Severity Index (PASI) \>=12
- •Static Physician's Global Assessment (sPGA) \>=3 (where scores range from 0 \[clear of disease\] to 5 \[severe disease\]) at the screening and baseline visits
- •Other protocol defined inclusion criteria could apply
Exclusion Criteria
- •Any condition, including protocol-specified laboratory findings and findings in the medical history or in the pre-trial assessments which in the Investigator's opinion constitutes a risk or a contraindication for the subject's participation in the trial or that could interfere with the trial objectives, conduct or evaluation
- •Currently having a form of non-plaque psoriasis as specified in the protocol
- •Drug induced psoriasis
- •Biological treatments as specified in the protocol, within 3 months prior to Day 1
- •Systemic immunosuppressants or phototherapy as specified in the protocol, within 1 month prior to Day 1
- •Use of anti-coagulant medications and/or antiplatelet medications as defined in the protocol
- •Use of aspirin as defined in the protocol
- •Topical corticosteroid treatments other than low-strength or lower-mid strength corticosteroids on the face, scalp, axillae, and/or groin within 1 month prior to Day 1
- •Any previous treatment with an agent targeting interleukin (IL)-17, IL-12 and/or IL-23 as specified in the protocol
- •Other protocol defined exclusion criteria could apply
Arms & Interventions
MSB0010841 30 mg
Intervention: MSB0010841
MSB0010841 60 mg
Intervention: MSB0010841
MSB0010841 120 mg
Intervention: MSB0010841
MSB0010841 240 mg
Intervention: MSB0010841
Placebo
Intervention: Placebo
Outcomes
Primary Outcomes
MSB0010841 Serum Concentration Over Time After First Dose
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Levels of Anti-MSB0010841 Antibody Titers
Time Frame: Day 8, 15 (pre-dose), 22, 29 (pre-dose), 36, 43, 63 and 85
Levels of Pre-existing Anti-MSB0010841 Antibody Titers
Time Frame: Pre-dose on Day 1
MSB0010841 Serum Concentration Over Time After Second Dose
Time Frame: 0 hours (pre-dose), 24, 72, 96, 168, 336 hours post-second dose (Day 15)
Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
Time Frame: Baseline up to Day 85
An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. TEAEs were the AEs occurring or worsening after treatment administration.
Number of Subjects With Local Injection Site Reactions (ISRs)
Time Frame: Day 1, 2,8, 15, 16, 22, 29, 30, 36, 43
The injection site was assessed by the Principal Investigator (PI) or his/her designee for local reactions such as redness, swelling, indurations or bruising, and by the subject for itching. Redness and bruising were scaled as None (no visible redness or bruising present); Mild (less than or equal to \[\<=\] 2.0 centimeters \[cm\] redness or bruising area); Moderate (greater than \[\>\] 2 to \<=5.0 cm redness or bruising area); Severe (\>5.0 cm redness or bruising area). Swelling was scaled as None (no swelling detected); Mild (palpable 'firmness' only); Moderate (\<= 4 cm swelling); Severe (\>4 cm swelling). Induration was scaled as None (no induration); Mild (able to move skin parallel to plane (sliding) and perpendicular to skin (pinching up); Moderate (able to slide skin, unable to pinch skin); Severe (unable to slide or pinch skin). Itching was scaled as No itching; Mild itching; Moderate itching and Severe itching. Subjects who reported any of the local ISRs were reported.
Amount of Pain at Injection Site Assessed By Visual Analog Scale (VAS)
Time Frame: Day 1, 2, 8, 15, 16, 22, 29, 30, 36, 43
Subjects were asked to assess their severity of injection site pain on a 100 millimeter (mm) VAS, where 0 = no pain and 100 = worst possible pain. Mean of amount of pain was calculated for the subjects having a value \> 0. Maximum values per subjects (over injection site areas) are used for counting the amount of pain at injection site. Maximum pain scores recorded among all participants analysed in each arm are reported for each time point.
Percentage of Subjects With Anti-MSB0010841 Binding Antibodies (Anti-Drug Antibodies [ADA])
Time Frame: Baseline up to Day 85
Data were presented for MSB0010841 combined group and placebo.
Observed Serum Concentration Immediately Before First Dose (Cpre) of MSB0010841
Time Frame: Pre-dose (0 hours) on Day 1
The observed serum concentration immediately before the first dose.
Observed Serum Concentration Immediately Before Third Dose (Cpre) of MSB0010841
Time Frame: Pre-dose (0 hours) on Day 29
The observed serum concentration immediately before the third dose.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above LLOQ.
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).
Area Under the Concentration-Time Curve From Time Zero up to Time Tau (AUCtau) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-third dose (Day 29)
Area under the concentration-time curve from time zero up to time Tau, where Tau is the dosing interval (336 hours).
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC 0-inf) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Area under the serum concentration-time curve from time zero to infinity (AUC0-inf). AUC0-infcalculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clast calc/λz, where Clast calc is the calculated concentration at the last sampling time point at which the measured concentration is at or above LLOQ and λz is the terminal rate constant determined from the terminal slope of the log transformed concentration curve using linear regression on terminal data points of the curve.
MSB0010841 Serum Concentration Over Time After Third Dose
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Area under the serum concentration-time curve (AUC) from time zero to the last sampling time point at which the concentration is at or above lower limit of quantification (LLOQ).
Mean Residence Time of Drug in the Body From Time Zero Extrapolated to Infinity (MRT(0-inf) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Mean residence time of drug in the body from time zero extrapolated to infinity, based on the last predicted concentration at tlast.
Minimum Concentration Observed (Cmin) During Third Dosing Interval of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.
Maximum Concentration Observed (Cmax) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Maximum Concentration Observed (Cmax) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Minimum Concentration Observed (Cmin) During First Dosing Interval of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
The observed minimum serum concentration determined directly from the serum concentration-time profile of each subject.
Average Concentration (Cav) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Cav was calculated by AUCtau/tau. Where tau is the dosing interval (336 hours).
Average Concentration (Cav) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Cav was calculated by AUCtau/tau. Where tau is the dosing interval (336 hours).
Mean Residence Time (MRT0-t) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC(0-t)/AUC(0-t) where AUMC(0-t) is area under the plasma concentration-time first moment curve from time zero to time t (336 hours) and AUC(0-t) is the area under the plasma concentration-time curve from time zero to tome t (336 hours).
Mean Residence Time (MRT0-t) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-third dose (Day 29)
MRT is the average time at which the number of absorbed molecules reside in the body, after single-dose administration, and calculated as AUMC(0-t)/AUC(0-t) where AUMC(0-t) is area under the plasma concentration-time first moment curve from time zero to time t (336 hours) and AUC(0-t) is the area under the plasma concentration-time curve from time zero to tome t (336 hours).
Time to Reach Maximum Observed Concentration (Tmax) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
Time to Maximum Observed Concentration (Tmax) Post Second Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 24, 72, 96, 168, 336 hours post-second dose (Day 15)
Apparent Terminal Half-life (t1/2) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life is calculated by dividing the natural logarithm to the base e (Log e) multiplied by (\*) 2/ λz, where 'λz' is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Terminal Rate Constant (λz) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Terminal rate constant was determined from the terminal slope of the logtransformed concentration curve using linear regression on terminal data points of the curve
Accumulation Ratio of Cmax (Racc (Cmax))
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1) and 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Accumulation ratio for Cmax was calculated as Cmax, after third dose / Cmax, after first dose.
Accumulation Ratio of AUC (Racc(AUC))
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1) and 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Accumulation ratio for AUC, calculated as area under the serum concentration-time curve within one complete dosing interval at third dose divided by area under the serum concentration-time curve within one complete dosing interval at first dose.
Maximum Observed Concentration (Cmax) Post Second Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 24, 72, 96, 168, 336 hours post-second dose (Day 15)
Observed Serum Concentration Immediately Before Second Dose (Cpre) of MSB0010841
Time Frame: Pre-dose (0 hours) on Day 15
The observed serum concentration immediately before second dose.
Time to Reach Maximum Observed Concentration (Tmax) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Apparent Clearance (CL/f) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
Apparent Volume of Distribution During Terminal Phase (Vz/f) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution during the terminal phase, calculated as Vz = Dose/AUC0-inf multiplied by elimination rate constant \[λz\]) following first dose and Dose/(AUCtau multiplied by λz) after third dose.
Percentage Peak-Trough Fluctuation (PTF) Post First Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336 hours post-first dose (Day 1)
The peak trough fluctuation within one dosing interval, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100
Percentage Peak-Trough Fluctuation (PTF) Post Third Dose of MSB0010841
Time Frame: 0 hours (pre-dose), 6, 12, 24, 32, 72, 96, 168, 336, 504, 816, 1056, 1344 hours post-third dose (Day 29)
The peak trough fluctuation within one dosing interval, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100
Secondary Outcomes
- Percentage of Subjects With 50% or 75% Improvement From Baseline in Psoriasis Area and Severity Index (PASI) Score(Baseline up to Day 85)
- Mean Change From Baseline in Psoriasis Area and Severity Index (PASI) Score at Day 43(Baseline, Day 43)
- Percentage of Subjects With Static Physician's Global Assessment (sPGA) Score of Minimal or Clear and With at Least 2 Level Reduction From Baseline(Day 8, 15, 22, 29, 36, 43, 50, 85)
- Mean Percent Change From Baseline in the Body Surface Area (BSA) Affected by Psoriasis at Day 8, 15, 22, 29, 36, 43, 50 and 85(Baseline, Day 8, 15, 22, 29, 36, 43, 50 and 85)
- Percentage of Subjects With Exacerbation of Psoriasis(Baseline up to Day 85)