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Autistic DisorderPhase 1NCT04475848

A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants

A Phase 1 study testing RO6953958 and Midazolam in people with Autistic Disorder and Autism Spectrum Disorder, run by Hoffmann-La Roche at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single- and multiple-ascending doses (SAD (Part 1) and MAD (Part 2)) and food effect (FE) of RO6953958 following oral administration in healthy male participants. Read more about this study

Who is it for?
Ages 18 to 55 years, men onlyHealthy volunteers can take part
What is being tested?
RO6953958 and Midazolam
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
88 participants
Where
1 siteUnited Kingdom
Study dates
15 Jul 2020to 6 Feb 2022
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • Men only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Body mass index (BMI) within 18 to 31 kg/m2
  • During treatment and for at least 14 days after the last dose to remain abstinent
  • Refrain from donating sperm for at least 14 days after last dose
  • Part 2 (MAD) only - Participants must be prepared to collect a sleep log and wear an actigraphy device the week before participation in the study. Participants must also have scored 5 or less on the Pittsburgh Sleep Quality Index (PSQI), less than 13 on the Epworth sleepiness scale (ESS), and not be considered an extreme morning or evening type according to the morningness-eveningness questionnaire (MEQ) at screening to be eligible.

Who cannot join

  • History or evidence of any medical condition potentially altering the absorption, metabolism, or elimination of drugs
  • History of any clinically significant gastrointestinal, renal, hepatic, bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological, hematological, or allergic disease, sleep disorders (Part 2 [MAD] only), unexplained syncope (within 12 months prior to screening), metabolic disorder, cancer, or cirrhosis
  • Use of any psychoactive medication, or medications known to have effects on central nervous system (CNS), or blood flow
  • History of convulsions
  • History of clinically significant hypersensitivity (e.g., drugs, excipients) or allergic reactions
  • Abnormal blood pressure (BP) and pulse rate
Show all 20Show fewer
  • Presence of orthostatic hypotension
  • History or presence of clinically significant ECG abnormalities or cardiovascular disease
  • Current or chronic history of liver disease or known hepatic or biliary abnormalities
  • Known active or any major episode of infection within 4 weeks prior to the start of drug administration
  • Participants who test positive for acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Have used or intend to use over-the-counter (OTC) or prescription medication including herbal medications within 30 days prior to dosing
  • Positive test for drugs, abuse of alcohol, human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus (HCV), presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test
  • Inability or unwillingness to fully consume standardized breakfast at Day 1
  • Part 2 (MAD) only - Participants who have issues sleeping or participants who have travelled across 2 or more time zones in the past month.
  • Part 2 (MAD) only - Participants who cannot produce sufficient saliva for study assessments
  • Participants who have donated more than 500 mL of blood or blood products or had significant blood loss within 3 months prior to screening
  • Have a history of clinically significant back pain, back pathology, and/or back injury that may predispose to complications from, or technical difficulty with, lumbar puncture
  • Complications that would lead to difficulty in obtaining a lumbar puncture
  • Part 3 (DDI) only - History of hypersensitivity to benzodiazepines (including midazolam) or its formulation ingredients

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • Hammersmith Medicines Research; Central Middlesex Hospital

    London, NW10 7EW

Other trials in United Kingdom

About this study

Official title: A Randomized, Investigator- /Subject-blind, Single- and Multiple-ascending Dose, Placebo-controlled Study to Investigate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 (Including RO6953958 Effect on Midazolam) Following Oral Administration in Healthy Male Participants

This study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single- and multiple-ascending doses (SAD (Part 1) and MAD (Part 2)) and food effect (FE) of RO6953958 following oral administration in healthy male participants. Part 3 (Drug-drug interaction (DDI)) will assess the safety, tolerability, and effect of RO6953958 on the PK of the cytochrome P450 (CYP) 3A substrate midazolam.

Being tested
RO6953958, Placebo, Midazolam
Keywords
Autism Spectrum Disorder
Medical subject headings
Autistic Disorder, Autism Spectrum Disorder, Child Development Disorders, Pervasive, Mental Disorders, Neurodevelopmental Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RO6953958Drug

    Part 1: RO6953958 will be administered in an adaptive manner. The starting dose is planned to be 5 milligrams (mg).

    Part 2: The starting dose is planned to be 45 mg.

    Part 3: RO6953958 will be administered QD following a standardized breakfast on Day 3 to Day 14 at the maximum dose QD that was tested in the ongoing Part 2 (MAD).

  • PlaceboDrug

    Part 1: A placebo will be administered in an adaptive manner. The starting dose is planned to be 5 mg.

    Part 2: The starting dose is planned to be 45 mg.

  • MidazolamDrug

    Midazolam will be administered as single intervenous (IV) bolus injection of 100 micrograms (ug) on Day 1 and Day 13, and as single oral dose of 300 ug on Day 2 and Day 14.

Study groups in NCT04475848
Study groupRoleWhat they receive
Part 1: SAD/FEExperimentalThere will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of RO6953958 while fasted. Participants in the fed (FE) cohort will return to receive the same single oral dose of RO6953958 repeated in the fed state.
Receives: Drug: RO6953958
Part 1: SAD placeboPlacebo comparatorThere will be 7 cohorts in this study. In each cohort, participants will receive a single oral dose of a placebo while fasted/fed.
Receives: Drug: Placebo
Part 2: MADExperimentalA maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of RO6953958 once daily (QD) for 10 days.
Receives: Drug: RO6953958
Part 2: MAD placeboPlacebo comparatorA maximum of 5 dose levels are anticipated. For each dose level, a minimum of 8 and a maximum of 16 participants will receive a multiple oral dose of palcebo QD for 10 days.
Receives: Drug: Placebo
Part 3: DDIExperimentalRO6953958 will be administered at the maximum dose QD that was tested in the ongoing Part 2 (MAD). Participants will also be administered midazolam.
Receives: Drug: RO6953958; Drug: Midazolam

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Parts 1, 2 and 3: Percentage of Participants With Adverse Events

    An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

    Measured: Part 1: From randomization up to 7 weeks (or up to 14 weeks if the participant is part of the food effect cohort). Parts 2 and 3: From randomization up to 8 weeks

  2. Part 2: Number of Participants With Post-baseline Suicide Risk, Assessed Using the Columbia Suicide Severity Rating Scale (C-SSRS)

    The C-SSRS is a questionnaire that is used to assess a participant's suicidal ideation and behaviors. The categories in the questionnaire have binary responses (yes/no) and include: Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Suicidal ideation or behavior is indicated by a "yes" answer to any of the listed categories. A score of 0 is assigned if no suicide risk is present. Categories with non-zero values are reported here.

    Measured: From randomization up to 8 weeks

Secondary outcomes (32)

  1. Parts 1, 2 and 3: Maximum Observed Plasma Concentration (Cmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  2. Parts 2 and 3: Average Plasma Concentration (Cavg) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  3. Parts 1, 2 and 3: Time to Reach Maximum Observed Plasma Concentration (Tmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  4. Part 1: Last Quantifiable Concentration (Clast) of RO6953958 and Its Metabolites RO7021594 and RO7045755 in Fasted and Fed State

    Measured: Day 1-10

  5. Part 1: Time To the Last Quantifiable Concentration (Tlast) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-10

  6. Parts 1, 2 and 3: Terminal Elimination Phase Half-Life (t1/2) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  7. Parts 2 and 3: Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  8. Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to 24h Postdose (AUC(0-24h)) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-5

  9. Part 1: Area Under the Plasma Concentration Versus Time Curve From Zero to the Last Measurable Concentration (AUC0-last) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-10

  10. Part 1: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-10

  11. Parts 1, 2 and 3: Apparent Clearance (CL/F) of RO6953958

    Measured: Day 1-14

  12. Parts 1, 2 and 3: Apparent Volume of Distribution (V/F) of RO6953958

    Measured: Day 1-14

  13. Parts 1 and 2: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of RO6953958

    Measured: Day 1 and 10

  14. Parts 1 and 2: Fraction of the Administered Drug Excreted Into the Urine (Fe) of RO6953958

    Measured: Day 1 and 10

  15. Parts 1 and 2: Renal Clearance of the Drug From Urine (CLR) of RO6953958

    Measured: Day 1 and 10

  16. Parts 2 and 3: Trough Plasma Concentration (Ctrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1, 3, 10, 12, 13

  17. Parts 2 and 3: Accumulation Ratio Based on AUC (RAUC) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  18. Parts 2 and 3: Accumulation Ratio Based on Cmax (RCmax) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  19. Parts 2 and 3: Accumulation Ratio Based on Ctrough (RCtrough) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  20. Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Cmax of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  21. Parts 1, 2 and 3: Molecular Weight Adjusted Metabolite-to-Parent Ratio for Area Under the Concentration-Time Curve (AUC(0-t)) of RO6953958 and Its Metabolites RO7021594 and RO7045755

    Measured: Day 1-14

  22. Part 3: Tmax of Midazolam

    A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.

    Measured: Day 1-14

  23. Part 3: Cmax of Midazolam

    A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.

    Measured: Day 1-14

  24. Part 3: T1/2 of Midazolam

    A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.

    Measured: Day 1-14

  25. Part 3: AUClast of Midazolam

    A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.

    Measured: Day 1-14

  26. Part 3: AUCinf of Midazolam

    A single IV dose of 100 ug midazolam was administered on Day 1 and Day 13. A single oral dose 300 ug of midazolam was administered on Day 2 and Day 14. RO6953958 was administrated once daily at 210 mg from Day 3 up to Day 14 so concomitantly with IV dose of midazolam on Day 13 and with oral dose of midazolam on Day 14.

    Measured: Day 1-14

  27. Part 3: VF of Oral Midazolam

    Measured: Day 2-14

  28. Part 3: RAUC of Midazolam

    Measured: Days 13 and 14

  29. Part 3: RCmax of Midazolam

    Measured: Days 13 and 14

  30. Part 3: CL: Total Plasma Clearance of IV Midazolam

    Measured: Days 1 and 13

  31. Part 3: Fraction Absorbed (F) of Midazolam

    F is stated as a fraction of 1.

    Measured: Days 2 and 14

  32. Part 3: Volume of Distribution Under Steady-state Conditions (Vss) of Midazolam

    Measured: Days 3 and 14

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Jul 2020
  2. Study start15 Jul 2020
  3. Primary completion6 Feb 2022
  4. Study completion6 Feb 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
88 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04475848
Sponsor's protocol ID
BP41695
Other IDs
2019-004486-41, 2019
Status last verified
Jul 2024
First submitted
13 Jul 2020
Last updated
10 Jul 2024
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm).

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing RO6953958 and Midazolam in people with Autistic Disorder and Autism Spectrum Disorder, run by Hoffmann-La Roche at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Parts 1, 2 and 3: Percentage of Participants With Adverse Events (time frame: Part 1: From randomization up to 7 weeks (or up to 14 weeks if the participant is part of the food effect cohort). Parts 2 and 3: From randomization up to 8 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04475848.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2024.

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