CT-37527-13-0124

Britannia Pharmaceuticals Ltd

200 Longwater Avenue, Green Park, Reading, United Kingdom, RG2 6GP

Clinical Operations, Britannia Pharmaceuticals Ltd, +44 01635 568400,

Clinical Operations, Britannia Pharmaceuticals Ltd, +44 01635 568400,

No

No

No

Final

11 Oct 2018

Yes

06 Jun 2016

Yes

08 Jun 2017

No

The primary objective is to investigate the efficacy of apomorphine subcutaneous infusion compared to placebo in PD patients with motor fluctuations not well controlled on medical treatment.

The abdominal skin must be checked at each visit. Any skin changes must be documented (counted and described). Before starting the infusion and at each visit, patients are to be reminded of strict hygiene, massages after removing the needle, rotation of insertion site, making use of the whole abdomen (if comfortable to the patient), do not leave needle in for >18 hours. If nodule formation is suspected to interfere with the absorption of the study drug, patients should be re-trained in identifying suitable insertion sites. When necessary and depending on local availability, the following additional methods are permitted: -ultrasound, -silicone patches or -massage devices including creams, as recommended by the national provider of apomorphine or by national treatment guidelines. Laboratory tests are performed at Screening, Baseline (V3) and at V6, V8 and V10 and during open-label V12, V13, V14 and V15. These will include full blood count with differential blood count, haptoglobin, bilirubin and LDH. In the case of a drop of hemoglobin by ≥1.5 g/dl compared to the previous test, hemolytic anemia must be ruled out. The urgency of intervention depends on the degree of the change and whether there are any concomitant laboratory changes suggestive of hemolytic anemia and must be judged by the investigator in charge of reviewing the blood test results. The patient must be asked to come for an unscheduled safety visit and have the following assessments: -clinical assessment for symptoms and signs of anemia, -full blood count with differential blood count, -Coombs test, -haptoglobin, -bilirubin, -LDH. If any findings suggest hemolytic anemia, an internist / hematologist must be consulted. If hemolytic anemia is confirmed, apomorphine must be stopped and the patient must be managed as advised by the consulted internist / hematologist. The patient must be discontinued from the study.

03 Mar 2014

No

Yes

Netherlands: 14

Spain: 26

United Kingdom: 20

Austria: 13

Denmark: 3

France: 11

Germany: 20

107

107

0

0

0

0

0

0

56

51

0

Double-blind phase

Randomised - controlled

A centralised randomisation was performed for the DBP. The random allocation of treatments to patients was done by the Biometrics Department of AMS according to their SOP. Three sets of sealed randomisation envelopes were prepared, which were to be stored securely unopened until after database lock for the DBP of the study): one copy was held by AMS drug safety, one copy by STADA drug safety, and the final set was distributed to Investigative sites.

Yes

Apomorphine hydrochloride

Solution for infusion in pre-filled syringe

Subcutaneous use

The starting dose for apomorphine subcutaneous infusion was 1 mg/hour during the first day of infusion. If no adverse effects occurred, the hourly flow rate was then be increased in the following manner: >By 0.5 to 1 mg/hour each day, until the end of Visit 3 or until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first. >At the weekly visits up to week 4 (V6): by 0.5 to 1 mg/hour per visit until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first.

Placebo

Solution for infusion in pre-filled syringe

Subcutaneous use

The starting dose for placebo will be 1 mg/hour during the first day of infusion. If no adverse effects occur, the hourly flow rate will then be increased in the following manner: >By 0.5 to 1 mg/hour each day, until the end of Visit 3 or until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first. >At the weekly visits up to week 4 (V6): by 0.5 to 1 mg/hour per visit until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first

Open-label phase

Not applicable

N/A

Yes

Apomorphine hydrochloride

Solution for infusion in pre-filled syringe

Subcutaneous use

The starting dose for apomorphine subcutaneous infusion was 1 mg/hour during the first day of infusion. If no adverse effects occurred, the hourly flow rate was then be increased in the following manner: >By 0.5 to 1 mg/hour each day, until the end of Visit 3 or until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first. >At the weekly visits up to week 4 (V6): by 0.5 to 1 mg/hour per visit until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first.

Apomorphine hydrochloride

Solution for infusion in pre-filled syringe

Subcutaneous use

The starting dose for apomorphine subcutaneous infusion was 1 mg/hour during the first day of infusion. If no adverse effects occurred, the hourly flow rate was then be increased in the following manner: >By 0.5 to 1 mg/hour each day, until the end of Visit 3 or until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first. >At the weekly visits up to week 4 (V6): by 0.5 to 1 mg/hour per visit until the maximum dose of 8 mg/hour or the highest tolerated hourly dose has been reached, whichever occurs first.

Apomorphine hydrochloride

Placebo

mITT analysis set - apomorphine

All randomised patients treated at least once with the study medication and had at least one post baseline observation for the primary endpoint.

mITT analysis set - placebo

All randomised patients treated at least once with placebo and had at least one post baseline observation for the primary endpoint.

Apomorphine hydrochloride

Placebo

Apomorphine continued treatment in OLP

Apomorphine naive

mITT analysis set - apomorphine

All randomised patients treated at least once with the study medication and had at least one post baseline observation for the primary endpoint.

mITT analysis set - placebo

All randomised patients treated at least once with placebo and had at least one post baseline observation for the primary endpoint.

Primary efficacy variable is the absolute change in time spent “OFF” from baseline (start of blinded treatment) to the end of 12 weeks double-blind treatment period based on patient diaries using MMRM mITT population. The mean reduction (improvement) of absolute 'OFF' time as reported by the patient using the Hauser diary.

Primary

From baseline to the end of 12 weeks double-blind treatment period.

mITT analysis set - apomorphine v mITT analysis set - placebo

105

Pre-specified

2-sided

A self-administered questionnaire (Patient Global Impression of Change) measuring personal general state of health since the start of the study.

Secondary

Change was measured from baseline to end of 12 weeks treatment period.

At the end of 12 weeks' double blind treatment 79.1% of apomorphine treated patients reported at least a minimal improvement in their general health state (using PGIC) compared with 23.5% of placebo-treated patients (p<0.0001).

mITT analysis set - apomorphine v mITT analysis set - placebo

105

Pre-specified

Change in time spent “ON” without troublesome dyskinesia over 24 hours at the End of the Double-Blind Phase (Visit 10) from Baseline. Measurement based on Patient Diaries Using MMRM mITT Population. The mean change in 'ON' time as reported by the patient using the Hauser diary.

Secondary

Change was measured from baseline to end of the 12 weeks treatment period.

mITT analysis set - apomorphine v mITT analysis set - placebo

105

Pre-specified

Adverse Events (AEs) were collected on an on-going basis from the day of written informed consent until the last patient visit required by the protocol.

19.0

Placebo DBP

Apomorphine DBP

Apomorphine naive in OLP

Apomorphine continued treatment in OLP