Clinical trial NCT04201080: A Trial to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous TRV250
Official title: A Phase 1, Two-part, Single Dose, Randomised, Double-blind, Placebo-controlled Parallel Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Subcutaneous TRV250 Following Glyceryl Trinitrate Infusion
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Migraines
Lead sponsor: Trevena Inc.
Sponsor class: INDUSTRY
First posted: 2019-12-17
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study consists of 2 parts: Part A is a proof of concept study; and Part B will be a dose ranging study
Primary purpose: OTHER

Brief summary: A trial to assess the efficacy, safety, tolerability and effect of a drug (code name TRV250) given as an injection to subjects who have received an injection of a drug called glyceryl trinitrate (GTN) which is clinically known to induce an immediate headache of short duration (under 30 minutes), known as the "GTN immediate headache"

Detailed description: This is a Phase 1, two-part, single dose, randomised, double-blind, placebo-controlled parallel study to evaluate the efficacy, safety, tolerability and pharmacokinetics of subcutaneous TRV250 following glyceryl trinitrate infusion-evoked migraine type headache.

Approximately 360 patients (120 in Part A and 240 in Part B) are planned to complete dosing and assessments.

Part A will be a proof of concept study; approximately 120 patients will be randomised to 1 of 2 treatments (60 patients per treatment arm). Patients will receive either TRV250 (20 mg) or placebo administered subcutaneously in a double-blind manner. Part B will be a dose-ranging study; approximately 240 patients will be randomised to 1 of 4 treatments (60 patients per treatment arm). Patients will receive 1 of 3 doses of TRV250 or placebo administered subcutaneously in a double-blind manner.

The study will consist of 3 phases: Screening, Confinement, and Follow-Up. Patients will participate in an outpatient Screening visit, a 3-day inpatient Confinement Phase that comprises GTN-infusion and treatment with TRV250 or placebo, and an outpatient safety Follow-Up visit 5 to 7 days post-dose.

The expected duration of participation is up to 6 weeks.

The diagnosis and criteria for inclusion covers male and female patients aged 18-55 years (inclusive), with a body mass index (BMI) within the range 18-32 kg/m2 inclusive at Screening. The patient must experience a migraine without aura as defined by International Headache Society (IHS) criteria 1.1 and experience between 1 migraine attack every other month to 8 migraine attacks per month. They should have had a positive outcome with Triptans, for their migraine attacks (Triptan Responders).

The investigational product (TRV250) will be administered by subcutaneous injection (10 mg/ml per injection). In Part A, 2 injections will be administered to deliver a single dose of 20 mg. In Part B, the dose levels to be administered will be decided following interim analysis of the data collected in Part A; however, the doses selected will not exceed that administered in Part A (up to 2 injections will be administered to deliver a single dose of up to 20 mg). Matched placebo injections will be administered by subcutaneous injections to maintain blinding.

By virtue of this being an exploratory study for the purpose of estimation and prediction, Bayesian estimates along with posterior predictive probabilities will be provided to address the primary and secondary efficacy objectives, as appropriate. Standard descriptive statistics will be provided to assess secondary safety and pharmacokinetic objectives.

Interim analyses will be conducted at the end of Part A of the study prior to proceeding to Part B. Preliminary pharmacokinetics (using nominal times) will be conducted to estimate the AUCt, AUC∞, Cmax, and t1/2. These preliminary efficacy, pharmacokinetic, safety and tolerability data will be evaluated unblinded at the end of Part A and shared with the Investigators in an unblinded manner, prior to starting Part B.

Once the study is complete, pharmacokinetic analyses will be completed using actual collection times.

In Part A, the difference in treatment proportions of patients who experience a headache occurring up to 4 hours post-dose will be tested using a chi-square. If the patient requires rescue medication then the patient will be considered a non-responder. In Part B, a Bayesian approach will be utilized using the prior information obtain from Part A. The proportion of patients who experience a headache occurring up to 4 hours post-dose, will be modelled using a Bayesian hierarchical logistic regression. This logistic regression will include a continuous covariate for TRV250 dose where Placebo is considered to be 0 mg of TRV250. If the patient requires rescue medication then the patient will be considered a non-responder.

Demographic and baseline data will be listed and summarised descriptively. Safety and tolerability assessments will be listed and summarised descriptively by treatment group as the observations and when appropriate, as the change from baseline. Plasma PK parameter values will be listed and summarised by treatment group. Dose proportionality may be assessed with a power model and slope analysis.

Safety laboratory tests will be tabulated and any out of range values highlighted. Clinically significant changes in safety laboratory results will be recorded as AEs.

Eligibility criteria: Inclusion Criteria:

* Patient is male or female, aged between 18 and 55 years inclusive.
* Patient's Body Mass Index (BMI) is between 18 and 32 kg/m2 inclusive.
* Patient should have a clinical diagnosis of migraine without aura (IHS criteria 1.1) and experience between 1 migraine attack every other month to 8 migraine attacks per month. They should have had a positive outcome with Triptans, for their migraine attacks (Triptan Responders).

Exclusion Criteria:

* Patient has previous exposure to TRV250.
* Abnormal EEG at screening or risk factors of increased seizure potential, such as previous seizures, history of febrile seizures, cerebral tumor, stroke, cerebrovascular disease, or significant traumatic brain injury.
* Patient with a history of hypotension or hypertension, including where this is currently under control.
* Patient taking prophylactic migraine treatments such as beta blockers 28 days before GTN infusion on Day 1.
* Resting heart rate \<45 beats per minute on assessment of vital signs at screening or pre-GTN infusion on Day 1.
* QTcF \>450 msec at screening (mean of three ECGs) or pre-GTN infusion on Day 1.
* Patient with another headache disorder such as menstrual migraine, chronic migraine, cluster headache, tension headache or other chronic headache states.
* Patient who have a history, or family history of any vascular intracranial lesion such as subarachnoid aneurysm or similar and patients with a relevant neurological history.
* Patients who have any allergies/contraindications for Triptan administration.

Primary outcomes:
measure: The primary outcome of this study is the proportion of patients who experienced a headache from dosing up to 4 hours post-dose, that exceeds a verbal numerical rating scale (NRS) headache rating of ≥2 points.
timeFrame: 0-4 hours post-dose
Secondary outcomes:
measure: The proportion of patients who experienced a headache occurring at various timepoints from dosing up to 8 hours post-dose, that exceeds a verbal NRS headache rating of ≥2 points
timeFrame: 0-8 hours post-dose
measure: The proportion of patients who experience a headache occurring at various timepoints from dosing up to 8 hours post-dose, that exceeds a verbal NRS headache rating of ≥3 points.
timeFrame: 0-8 hours post-dose
measure: The proportion of patients who experience a headache occurring at various timepoints from dosing up to 8 hours post-dose, that exceeds a verbal NRS headache rating of ≥4 points.
timeFrame: 0-8 hours post-dose
measure: Pain Response (PR) at 2-hour time point following injection of TRV250 or placebo
timeFrame: every 2 hours for 24 hours
measure: PF at 2-hour time point following injection of TRV250 or placebo.
timeFrame: every 2 hours for 24 hours
measure: Sustained pain response between 2 and 24 hours (2-24H SPR): PR at 2 hours after TRV250 or placebo administration, with no administration of any rescue medication and no occurrence of migraine type headache with verbal NRS score of ≥4 points
timeFrame: up to 24 hours post dose
measure: Absence of nausea between 2 and 24 hours in patients with nausea from 60 minutes post-start of GTN infusion
timeFrame: up to 24 hours post dose
measure: Absence of photophobia between 2 and 24 hours in patients with photophobia from 60 minutes post-start of GTN infusion.
timeFrame: up to 24 hours post dose
measure: Proportion of patients requiring use of rescue medication at various timepoints.
timeFrame: up to 24 hours of follow-up
measure: The effect of TRV250 on cardiac repolarisation determined from cardiac telemetry
timeFrame: Continuous Cardiac Telemetry: min 8hrs pre-GTN to 24hrs post dose
measure: The effect of TRV250 on cardiac repolarisation (Cardiac Telemetry)
timeFrame: Continuous Cardiac Telemetry: min 8hrs pre-GTN to 24hrs post dose
measure: The effect of TRV250 on cardiac repolarisation (Electrocardiogram)
timeFrame: 12-lead ECG: screening, Day-1 and up to 24 hours post dose
measure: Safety Assessment - Injection Site Assessment
timeFrame: at time of GTN-infusion (0 hours) up to 24hrs post-dose
measure: The PK data model for each patient/dose combination: AUC(0-∞)
timeFrame: up to 24 hours post dose
measure: The PK data model for each patient/dose combination: AUC(0-24)
timeFrame: up to 24 hours post dose
measure: The PK data model for each patient/dose combination: Cmax (ng/mL) o Tmax - Time of maximum concentration (hours) o t1/2 - half-life (hours)
timeFrame: up to 24 hours post dose
measure: The PK data model for each patient/dose combination: Tmax
timeFrame: up to 24 hours post dose
measure: The PK data model for each patient/dose combination: t1/2
timeFrame: up to 24 hours post dose
Other outcomes:
measure: Migraine headache relapse defined as a verbal NRS headache score ≥4 points from the timepoint of Pain Response (PR) through 24 hours of follow-up.
timeFrame: up to 24 hours of follow-up
measure: Sustained pain freedom between 2 and 24 hours (2-24H SPF).
timeFrame: 2-24 hours post dose
measure: Two-hour total migraine freedom (2H TMF; migraine freedom is defined as PF + no nausea + no vomiting + no photophobia + no phonophobia): TMF at 2-hour time point.
timeFrame: 2-hours
measure: Two-hour total migraine freedom (2H TMF; migraine freedom is defined as PF + no nausea + no vomiting + no photophobia + no phonophobia): TMF at 2-hour time point.
timeFrame: up to 24 hours of follow-up
measure: Total migraine freedom between 2 and 24 hours (2-24H TMF): 2H + no nausea + no vomiting + no photophobia + no phonophobia between 2 hours and 24 hours after TRV250 or placebo administration.
timeFrame: up to 24 hours of follow-up
measure: Time to pain response (TTPR).
timeFrame: 0-8 hours and up to 24 hours of follow-up
measure: Time to pain freedom (TTPF).
timeFrame: 0-8 hours and up to 24 hours of follow-up
measure: Acute migraine type headache characteristics evoked with GTN infusion compared with spontaneous migraine.
timeFrame: up to 24 hours of follow-up
measure: Number of evoked headaches that have at least 2 of the 4 migraine characteristic criteria (IHS 1.1 - Criteria C) and have at least 1 of the 2 associated headache criteria (IHS 1.1 - Criteria D).
timeFrame: up to 24 hours of follow-up
measure: Number of evoked headaches that have at least 2 of the 4 migraine characteristic criteria (IHS 1.1 - Criteria C).
timeFrame: up to 24 hours of follow-up
measure: Number of evoked headaches that have at least 1 of the 2 associated headache criteria (IHS 1.1 - Criteria D).
timeFrame: up to 24 hours of follow-up
measure: Anxiety monitoring using
timeFrame: up to 24 hours of follow-up
measure: Orthostatic assessments - Blood Pressure
timeFrame: at 4 hours post-dose
measure: Orthostatic assessments - Heart Rate
timeFrame: at 4 hours post-dose
Locations:
city: Manchester
country: United Kingdom
facility: MAC Clinical Research Manchester (Early Phase Unit), Neuroscience Centre of Excellence
state: Greater Mancherster
Study officials:
affiliation: MAC Clinical Research Manchester (Early Phase Unit)
name: Dasyam, MBBS, Msc
role: PRINCIPAL_INVESTIGATOR
affiliation: Trevena Inc.
name: Nicklas, RN BSN CCRC
role: STUDY_DIRECTOR
References: