A Phase IIa Withdrawal Study of CNV1014802 in Patients With Trigeminal Neuralgia

A Phase IIa Placebo-Controlled, Double-Blind Randomized Withdrawal Study to Evaluate the Safety and Efficacy of CNV1014802 in Patients With Trigeminal Neuralgia

This is a double-blind, randomized withdrawal study comparing CNV1014802 with placebo in patients with trigeminal neuralgia who have successfully responded to CNV1014802 in an initial open-label phase.

Patients will participate in an initial open-label treatment period of 21 days of CNV1014802 150mg three times a day (tid). Responders will be randomized to 28 days of CNV1014802 150mg tid or placebo.

Following an interim analysis after 10 evaluable patients have completed the open-label phase, the dose regimen may be increased to 350mg twice a day (bid) for the remainder of the trial if the responder rate is less than 60%.

Study Overview

• Status: Completed
• Conditions: Trigeminal Neuralgia
• Intervention / Treatment: Drug: CNV1014802; Drug: Placebo

Detailed Description

In order to be randomised and enter the double-blind placebo controlled phase of the study, patients must satisfy at least one of the following criteria:

• 30% or more decrease in number of paroxysms (either spontaneous, evoked, or both)
• 30% reduction in the severity of pain experienced during the paroxysm (either spontaneous, evoked or both)
• A Patient Global Improvement of Change rating of much improved/very much improved The response will be compared with the baseline recordings of pain made in the 7 day run-in period. If a patient meets one of these criteria they are termed a responder, and will be eligible to be randomized into the double-blind treatment phase.

During the double-blind randomised phase, patients will be evaluated to determine if they meet the failure criteria at each clinic visit which will occur every 7 days in the double-blind treatment period. The number of failures on CNV1014802 versus number of failures on placebo during the double-blind treatment period will be the primary outcome of the study.

Patients will be classified as a treatment failure if they meet one of the following criteria:

• 50% increase in the frequency of paroxysms compared to the final 7 days of the open-label period
• 50% increase in the severity of pain experienced in the paroxysms compared to the final 7 days of the open-label period
• A Patient Global Improvement of Change rating of much worse/very much worse
• The patient discontinues the study due to 'Lack of Efficacy'
• The patient discontinues due to an adverse reaction or poor tolerability considered to be related to study medication

This study was previously posted by Convergence Pharmaceuticals, Ltd., which has been acquired by Biogen.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Professor Joanna Zakrzewska

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female aged between 18 and 70 years, with a diagnosis of trigeminal neuralgia; IHS criteria to be used.
• Female patients must be of non-child bearing potential or agree to use an approved form of contraception
• Male patients must agree to use an approved form of contraception
• Body weight > 50 kg for men and > 45 kg for women.
• BMI ≤ 34.9
• Capable of giving written informed consent. Informed consent must be obtained prior to the commencement of any study related procedures.
• QTcB either/or QTcF < 450 msec in two of three ECGs conducted at screening
• AST and ALT < 2xULN; alkaline phosphatase and bilirubin < 1.5xULN.
• Approved concomitant medications must have been stable for at least 3 weeks prior to day 0.

Exclusion Criteria:

• Patients who are known non-responders to sodium channel blockers at therapeutic doses.
• Patients with causes for their facial pain other than that specified in Inclusion Criterion
• A positive pre-study drug screen.
• A positive history of HIV.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• History of any liver disease within the last 6 months, with the exception of known Gilbert's disease.
• History of excessive regular alcohol consumption within 6 months of the study.
• Patients with a history or risk of seizures or a history of epilepsy, head injury or related neurological disorders
• Patients with a history of uncontrolled or poorly controlled hypertension, with systolic BP frequently exceeding 160mmHg and/or diastolic BP frequently exceeding 100mmHg, or patients who have BP greater than or equal to 160mmHg systolic and/or greater than or equal to 100mmHg diastolic at screening after repeated measurements
• History or presence of significant cardiovascular, gastro-intestinal, or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
• Patients with conditions known to affect cardiac conduction or a personal or familial history of Brugada syndrome
• Pregnant females or lactating females.
• History or presence of any clinically significant abnormality in vital signs/ECG/laboratory tests or have any medical or psychiatric condition, which, in the opinion of the Investigator may interfere with the study procedures or compromise patient safety.
• History of suicidal ideation and/or suicide attempts or clinical evidence of recent major depression.
• Patients who are unable to maintain approved medications for their trigeminal neuralgia at a stable dose during the study.
• Unable to refrain from excessive use of sedatives.
• Unable to comply with the prohibited concomitant medication restrictions as detailed in the protocol. This includes but is not limited to sodium channel blockers or drugs that adversely interact with a monoamine oxidase-B inhibitor: MAOI's, antidepressants, opioids and sympathomimetic agents.
• History of hypersensitivity to CNV1014802.
• The patient has participated in a clinical trial and has received an investigational product within 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to the start of this study.
• Exposure to more than four new chemical entities (medications for which no marketing authorization has been obtained) within 12 months prior to the first dosing day.
• Where participation in the study would result in total donation of blood or blood products in excess of 500mL within a 56 day period.
• Patient is mentally or legally incapacitated.
• Unwillingness or inability to follow the procedures outlined in the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Double-blind placebo comparator for 28 days.
EXPERIMENTAL: CNV1014802	Drug: CNV1014802; CNV1014802 150mg tid for 28 days. Dose may be increased to 350mg bid following interim evaluation of efficacy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of failures on CNV1014802 vs. number of failures on placebo during the double-blind treatment period will be the primary outcome of the study.	Patients will be classified as a treatment failure if they meet one of the following criteria: 50% increase in the frequency of paroxysms compared to the final 7 days of the open-label period; 50% increase in the severity of pain experienced in the paroxysms compared to the final 7 days of the open-label period; A Patient Global Improvement of Change rating of much worse/very much worse; The patient discontinues the study due to 'Lack of Efficacy'. v. The patient discontinues due to an adverse reaction or poor tolerability considered to be related to study medication	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary pain endpoints	Number and severity of paroxysms of pain in the 21 day open-label period, both evoked and spontaneous; Average 24 hour pain intensity numerical rating scale (PI-NRS); Patient and Physician Clinical Global Impression of Change; Brief Pain Inventory - Facial	4 weeks

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Zakrzewska JM, Palmer J, Ettlin DA, Obermann M, Giblin GM, Morisset V, Tate S, Gunn K. Novel design for a phase IIa placebo-controlled, double-blind randomized withdrawal study to evaluate the safety and efficacy of CNV1014802 in patients with trigeminal neuralgia. Trials. 2013 Nov 23;14:402. doi: 10.1186/1745-6215-14-402.
• Zakrzewska JM, Palmer J, Bendtsen L, Di Stefano G, Ettlin DA, Maarbjerg S, Obermann M, Morisset V, Steiner D, Tate S, Cruccu G. Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: the trigeminal neuralgia experience. Trials. 2018 Dec 27;19(1):704. doi: 10.1186/s13063-018-3045-1.
• Zakrzewska JM, Palmer J, Morisset V, Giblin GM, Obermann M, Ettlin DA, Cruccu G, Bendtsen L, Estacion M, Derjean D, Waxman SG, Layton G, Gunn K, Tate S; study investigators. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 2017 Apr;16(4):291-300. doi: 10.1016/S1474-4422(17)30005-4. Epub 2017 Feb 17.

Helpful Links

• EudraCT Tabulated Result

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 31, 2012
• Primary Completion (ACTUAL): March 31, 2014
• Study Completion (ACTUAL): June 30, 2014

Study Registration Dates

• First Submitted: February 23, 2012
• First Submitted That Met QC Criteria: February 28, 2012
• First Posted (ESTIMATE): February 29, 2012

Study Record Updates

• Last Update Posted (ACTUAL): January 10, 2019
• Last Update Submitted That Met QC Criteria: January 7, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Stomatognathic Diseases; Mouth Diseases; Peripheral Nervous System Diseases; Cranial Nerve Diseases; Facial Nerve Diseases; Trigeminal Nerve Diseases; Facial Neuralgia; Neuralgia; Trigeminal Neuralgia
• Other Study ID Numbers: CNV1014802/202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No