E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic hypersomnia (IH) |
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E.1.1.1 | Medical condition in easily understood language |
Idiopathic hypersomnia (IH) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028714 |
E.1.2 | Term | Narcolepsy and hypersomnia |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part A: The primary objective is to assess the safety and tolerability of GR3027 after a single oral dose of GR3027 in female patients with IH.
Part B: The primary objective is to assess the safety and tolerability of GR3027 after multiple dose administration in patients with IH. |
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E.2.2 | Secondary objectives of the trial |
Part A: The secondary objective is to determine the single oral dose PK characteristics of GR3027 in female patients with IH.
Part B: The secondary objectives are to evaluate the exploratory efficacy of GR3027 after multiple dose administration in patients with IH and to assess the exposure of GR3027 at steady state in patients with IH.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have signed and dated an informed consent prior to beginning protocol required procedures.
2. In part A, females age 18 to 55 years. In part B, males or females age 18 to 55 years.
3. Meets the International Classification of Sleep Disorders criteria 3rd edition (ICSD-3) for the diagnosis of IH. The diagnosis is either done during screening or if within the last twelve months (as long as medical records are available for verification).
4. ESS of 11 or greater (as assessed at the screening visit)
5. An apnea-hypopnea index (AHI) < 15 within the last 12 months.
6. Patients on current treatment for their hypersomnolence disorder may be enrolled after discontinuing the medication and a washout phase (at least 5 x half-lives of medication but not less than 14 days). The following exception from the 14 days washout is allowed: 5 days washout for modafinil treatment prior to baseline.
7. Fertile female patients, willing to use a hormonal or non-hormonal intrauterine device (IUD) or condom together with a medically accepted method of birth control (diaphragm, sponge, cervical cap) or sexual abstinence and agree to continue use of this method for the duration of the study and thereafter for one month after the last dosing of the IMP. Fertile female patients using hormonal IUD must have had the IUD for at least a month and should plan to keep it during the study.
8. Fertile male patients must be willing to use condom and contraceptive methods with a failure rate of < 1% to prevent pregnancy1 and drug exposure of a fertile female partner and refrain from donating sperm from the date of dosing until one month after dosing of the IMP.
9. Women who are surgically sterile or two years post-menopausal may be included without fulfilling the above criteria on birth control.
10. Men who are surgically sterile may be included without they/their partner fulfilling the above criteria on birth control. |
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E.4 | Principal exclusion criteria |
1. History of pathological EEG as judged by the Investigator.
2. Pathological ECG at screening as judged by the Investigator.
3. Inability to swallow the required number of study medication capsules or otherwise comply with study procedures.
4. Any concurrent illness which at the discretion of the Investigator would compromise patient safety and/or compromise the objectives outlined in the protocol. These could include but are not limited to cardiovascular, endocrine, neoplastic, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurological (other than narcolepsy/hypersomnia), psychiatric (incl. but not limited to depression, anxiety), pulmonary, and/or renal disease.
5. Women with significant menstrual cycle related hypersomnolence (including premenstrual dysphoric syndrome (PMDS)).
6. History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to GR3027.
7. Current or recent (within one year) history of abuse of drugs of abuse including alcohol, anabolic steroids or as defined by the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders).
8. Positive screen for drugs of abuse at screening or at baseline prior to administration of the study treatment.
9. Female patients who are pregnant or nursing.
10. Abnormal renal or hepatic function as reflected by a serum creatinine > 2.0 mg/dL (177 micromol/L) or abnormal liver biochemical tests (AST or ALT > 2 x upper limit of normal) or serum bilirubin (more than 1.5 times upper limit of normal).
11. Evidence of active chronic viral infection including hepatitis B (serum hepatitis B surface antigen positive), hepatitis C (e.g. HCV RNA positive), and/or Human Immunodeficiency Virus (HIV positive).
12. Have an occupation that requires variable shift work or routine night shift.
13. Participation in any other clinical study that included drug treatment with the last administration within the past 30 days or five half-lives (whichever is longer) prior to administration of study treatment in this study. Patients consented and screened but not dosed in previous clinical studies are not excluded.
14. Use of hypnotics, stimulants, tranquilizers, antihistamines (except for non-sedating antihistamines), benzodiazepines or clonidine at the within 14 days prior to enrolment or during the study. Patients taking anticonvulsants for epilepsy are not eligible to participate even if they are willing to washout anticonvulsants for the study.
15. Concomitant drugs that are metabolised by either CYP3A4, CYP2C8 or CYP2C9 and where there is a risk for drug-drug interactions will be prohibited during the study, as judged by the Investigator.
16. Use of over the counter (OTC) products, prescription medications or off label medications for hypersomnolence disorders must be discontinued at least 5 x half-lives of the medication but not less than 14 days prior to baseline. The following exception from the 14 days washout is allowed: 5 days washout for modafinil treatment prior to baseline.
17. Regular or recent (i.e. within 14 days prior to enrolment) use of any prescribed or nonprescribed medications which, at the discretion of the Investigator, might compromise safe patient participation in the study and/or interpretation of the study results.
18. Unsuitable for the study as judged by Investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A:
Safety will be assessed by occurrence and frequency of AEs, SAEs, laboratory parameters, vital signs, ECG and physical examination.
Part B: Safety will be assessed by occurrence and frequency of AEs, SAEs, laboratory parameters, vital signs, ECG and physical examination. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: During 24h, 48h and day 8
Part B: During the treatment days and treatment day 7 and day 14 and 14 days after cross over last dose |
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E.5.2 | Secondary end point(s) |
Part A: The following PK parameters will be determined: Area under the plasma concentration curve (AUC) 0->∞, AUCt, maximum concentration (Cmax), time to maximum concentration (Tmax), lambdaz, terminal half-life (T1/2), apparent total body clearance following extra vascular administration (CL/F), apparent volume distribution/fraction of drug absorbed (Vz/F).
Part B:
Exposure measured as pre-dose values (Cmin) of GR3027 at steady state.
The following efficacy end points will be used to address the efficacy objective:
- Change in Epworth Sleepiness Scale (ESS) from baseline to week 2 of each treatment period while taking placebo versus GR3027.
- Change in Maintenance of Wakefulness Test (MWT) from baseline to week 2 of each treatment period while taking placebo versus GR3027. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: During 24h and 48h
Part B:
• PK results Cmin in week 2 of each treatment period
• Efficacy end point change from baseline to week 2 of each treatment period |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part A is an open, single dose study. Part B is randomised, double blind, cross over study. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |