Efficacy and Tolerability of AP707 in Patients with chronic Pain due to traumatic or post-operative peripheral Neuropathy

2022-500898-13-00 Protocol DISCOVER_(PNP2) Therapeutic confirmatory (Phase III) Ended

Start 2 Nov 2023 · End 10 Mar 2026 · Status Ended · 2 EU/EEA countries · 47 sites · Protocol DISCOVER_(PNP2)

Overview

Sponsor-declared trial summary

Phase Therapeutic confirmatory (Phase III)
Status Ended
Participants planned 558
Countries 2
Sites 47

Chronic Pain due to traumatic or post-operative peripheral Neuropathy

Evaluation of efficacy of AP707 as add-on treatment in patients with chronic pain due to traumatic or post-operative peripheral Neuropathy

Key facts

Sponsor
Cannaxan GmbH, Apurano Pharmaceuticals GmbH
Participant type
Patients
Age range
18-64 years, 65+ years
Gender
Male and Female
Therapeutic area
Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]
Trial duration
2 Nov 2023 → 10 Mar 2026
Decision date (initial)
2023-04-11
Transition trial
No
Low-intervention
No
Rare-disease indication
No
Vulnerable population
No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Evaluation of efficacy of AP707 as add-on treatment in patients with chronic pain due to traumatic or post-operative peripheral Neuropathy

Secondary objectives 1

  1. Evaluation of safety and tolerabilty of AP707

Conditions and MedDRA coding

Chronic Pain due to traumatic or post-operative peripheral Neuropathy

Regulatory references

Scientific advice from competent authorities
Federal Joint Committee, Federal Institute For Drugs And Medical Devices

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

  1. Signed and dated informed consent form
  2. Patients with chronic pain due to traumatic or post-operative peripheral Neuropathy since at least 3 months
  3. Female and male patients (≥ 18 years)
  4. Patients with more than 1 year life expectancy
  5. Patients with optimized sCPT on study entry as defined in section 3.1.1 and section 3.1.3 of the study protocol
  6. Willingness of study patients of both sexes to use reliable contraception during study participation and for three months after taking the last study medication
  7. Good command of German language, in order to understand questionnaires in German
  8. Current moderate to severe pain with pain intensity ≥ 5 on Numeric Rating Scale (NRS, 0 - 10) and thus an existing need for further pain therapy
  9. Completed QUISS (Quantification Inventory for Somatoform Syndromes) questionnaire with 45 or less score points

Exclusion criteria 15

  1. Medical history of hypersensitivity or intolerance to the investigational product or its ingredients or to ingredients of similar chemical structure
  2. Known intolerance to cannabinoids or cannabis products
  3. Participation in another clinical trial within the last four weeks prior to inclusion
  4. Pregnant or nursing women (as excluded by pregnancy testing at visit 1 for women of childbearing potential)
  5. Other medical conditions that do not allow the trial subject to appraise the nature, scope, and potential consequences of the clinical trial
  6. Indications that the trial subject is unlikely to comply with the study protocol (e.g., unwillingness to cooperate)
  7. Known use of medicinal cannabis products within the last 8 weeks
  8. Active malignant tumor disease, tumor pain, or other dominant severe pain other than that of the study indication
  9. Known history of severe liver or kidney diseases
  10. Known history of severe cardiovascular disease
  11. Known history of or acute mental illness such as severe depression, psychosis, bipolar disorder, mania, anxiety, or obsessive-compulsive disorder
  12. Known history of addictive disease (e.g., alcohol, medication, drug addiction)
  13. Answered during Screening less than 12 times of 18 the pain intensity (NRS) inquiry
  14. Laboratory liver values: Alanine aminotransferase (ALT, GPT) > 3 x ULN (Upper Limit of Normal range), Aspartate aminotransferase (AST, GOT) > 3 x ULN, Alkaline phosphatase (AP) > 2.5 x ULN, and for bilirubin > 1.5 x ULN
  15. Laboratory renal value: Serum creatinine > 1.5 ULN

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

  1. 1) Change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and at treatment week 14 (end of first treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo)

Secondary endpoints 15

  1. 2) Change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and at treatment week 26 (end of second treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo)
  2. 3) Change in pain level on the Numeric Rating Scale (NRS, 0-10) between baseline and at treatment week 52 (end of third treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo)
  3. 4) Change in the pain score of the Neuropathic Pain Symptom Inventory (NPSI) questionnaire between baseline established in the last week before start of randomized treatment and at treatment week 14 (end of first treatment phase), at treatment week 26 (end of second treatment phase), and at treatment week 52 (end of third treatment phase) in comparison of study arm 1 (verum) and study arm 2 (placebo)
  4. 5) Change in pain level on the Numeric Rating Scale (0-10) between baseline and in treatment week 5, 11, 18, 22, 30, 34, 43, 47 in comparison of study arm 1 (verum) and study arm 2 (placebo)
  5. 6) Responder analysis for endpoints 1), 2), 3) and 4) for treatment week 14, 26 and 52: 1. Proportion of patients who experienced > 30 % improvement in pain score (Numeric Rating Scale); 2. Proportion of patients who experienced > 40 % improvement in pain score (Numeric Rating Scale); 3. Proportion of patients who experienced > 50 % improvement in pain score (Numeric Rating Scale)
  6. 7) Change in sCPT (percentage of change in dosage and percentage of change in combination of analgesic measures) in both study arms from start to week 14
  7. 8) Change in psychological distress using Depression Anxiety Stress Scales Short Form (DASS-21) questionnaire from baseline established in the last week before start of randomized treatment to week 14, 26, and 52
  8. 9) Change of Patient Global Impression of Change (PGIC) from start to week 14, 26, and 52
  9. 10) Change in quality of life using the Veterans RAND (VR-12) questionnaire from baseline established in the last week before start of randomized treatment to week 14, 26, and 52
  10. 11) Change in sleep quality using the Regensburg Insomnia Scale (RIS) from baseline established in the last week before start of randomized treatment to week 14, 26, and 52
  11. 12) Change in pain score of the Brief Pain Inventory - Short Form (BPI-SF) questionnaire from baseline established in the last week before start of randomized treatment to week 14, 26, and 52
  12. 13) Area under NRS-curve until treatment week 5, 11, 14, 18, 22, 26, 30, 34, 39, 43, 47, 52
  13. 14) Change in VR-12 components (physical component summary PCS, mental component summary MCS) from baseline established in the last week before start of randomized treatment to week 14, 26, and 52
  14. 15) Number of patients with rescue medication over the course of the clinical trial and within periods: until treatment week ≤5, ≤11, ≤14, ≤18, ≤22, ≤26, ≤30, ≤34, ≤43, ≤47, ≤52
  15. 16) Number and severity of adverse events (AE)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Adezunap

PRD10071357 · Product

Active substance
Adezunap
Pharmaceutical form
OROMUCOSAL SPRAY, SUSPENSION
Route of administration
SUBLINGUAL USE
Max daily dose
20.83 ml millilitre(s)
Max total dose
923.32 ml millilitre(s)
Max treatment duration
52 Week(s)
Authorisation status
Not Authorised
ATC code
N02BG10 — -
MA holder
CANNAXAN GMBH
Paediatric formulation
No
Orphan designation
No

Placebo 1

Pump spray for sublingual application in 20 mL pump spray bottles. The placebo contains all excipients of AP707 without the addition of cannabis sativa (active ingredient). The appearance of the preparation is a brown-beige with a characteristic sweet and slightly fruity odor.

N/A · Product

Other product name
N/A
Pharmaceutical form
N/A
ATC code
N/A — N/A
Marketing authorisation
N/A
MA holder
N/A
MA country
Iceland
Paediatric formulation
No

Auxiliary 7

Buclizine Hydrochloride

SCP1081917 · ATC

Active substance
Buclizine Hydrochloride
Substance synonyms
Buclizine dihydrochloride
Route of administration
OTHER USE
Max daily dose
4000 mg milligram(s)
Max total dose
500 mg milligram(s)
Max treatment duration
56 Week(s)
Authorisation status
Authorised
ATC code
N02BE01 — PARACETAMOL
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Imipramine Hydrochloride

SCP199291 · ATC

Active substance
Imipramine Hydrochloride
Route of administration
ORAL
Max daily dose
300 mg milligram(s)
Max total dose
999999999999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max treatment duration
9999999 Month(s)
Authorisation status
Authorised
ATC code
N06AA02 — IMIPRAMINE
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

-

N02A · Product

Pharmaceutical form
-
Route of administration
OTHER USE
Max daily dose
99999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max total dose
9999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max treatment duration
9999999 Month(s)
Authorisation status
Authorised
ATC code
N02A — OPIOIDS
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Gabapentin

SCP135420 · ATC

Active substance
Gabapentin
Route of administration
ORAL
Max daily dose
3600 mg milligram(s)
Max total dose
999999999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max treatment duration
9999999 Month(s)
Authorisation status
Authorised
ATC code
N03AX12 — GABAPENTIN
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Amitriptyline

SCP813617 · ATC

Active substance
Amitriptyline
Route of administration
ORAL
Max daily dose
150 mg milligram(s)
Max total dose
9999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max treatment duration
9999999 Month(s)
Authorisation status
Authorised
ATC code
N06AA09 — AMITRIPTYLINE
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Capsaicin

SCP160424 · ATC

Active substance
Capsaicin
Route of administration
CUTANEOUS USE
Max daily dose
2.2 mg milligram(s)
Max total dose
99999999999999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max treatment duration
9999999 Month(s)
Authorisation status
Authorised
ATC code
N01BX04 — CAPSAICIN
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

-

N03AX · Product

Pharmaceutical form
PHF00082MIG
Route of administration
ORAL
Max daily dose
600 mg milligram(s)
Max total dose
99999999999999999999999999999999999999999999999999999999999999999999999 Kg kilogram(s)
Max treatment duration
9999999 Month(s)
Authorisation status
Authorised
ATC code
N03AX — OTHER ANTIEPILEPTICS
Marketing authorisation
-
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Cannaxan GmbH

4 Total trials 4 Ended
Commercial
Sponsor organisation
Cannaxan GmbH
Address
Birkerfeld 12, Lochham Lochham
City
Warngau
Postcode
83627
Country
Germany

Scientific contact point

Organisation
Cannaxan GmbH
Contact name
Medical Affairs

Public contact point

Organisation
Cannaxan GmbH
Contact name
Medical Affairs

Apurano Pharmaceuticals GmbH

5 Total trials 4 Ended
Commercial
Sponsor organisation
Apurano Pharmaceuticals GmbH
Address
Birkerfeld 12, Lochham Lochham
City
Warngau
Postcode
83627
Country
Germany

Scientific contact point

Organisation
Apurano Pharmaceuticals GmbH
Contact name
Medical Affairs

Public contact point

Organisation
Apurano Pharmaceuticals GmbH
Contact name
Medical Affairs

Locations

2 EU/EEA countries · 47 investigational sites

By country

CountryMS statusPlanned subjectsSites
Austria Ended 74 8
Germany Ended 484 39
Rest of world — 0 —

Investigational sites

Austria

8 sites · Ended
Klinik Oberwart
Department of Neurology, Dornburggasse 80, 7400, Oberwart
Kepler Universitaetsklinikum GmbH
Clinic for Neurology 2, Krankenhausstrasse 7a, 4020, Linz
Schmerzkompetenzzentrum
Pain Competence Center, Badner Straße 8, 2540, Bad Vöslau
Klinikum Wels-Grieskirchen GmbH
Department for Neurology, Grieskirchner Straße 42, 4600, Wels
Medical University Of Vienna
Dept. of Anaesthesia, Intensive Care Medicine and Pain Medicine, Division of Special Anaesthesia, Waehringer Guertel 18-20, Alsergrund, Vienna
Noe LGA Gesundheit Region Mitte GmbH
Clinical Department of Neurology, Alter Ziegelweg 10, 3430, Tulln An Der Donau
Klinikum Klagenfurt Am Woerthersee
Department of Anesthesiology and Intensive Care Medicine, Feschnigstrasse 11, Klagenfurt,09.Bez.:Annabichl, Klagenfurt Am Woerthersee
Oberoesterreichische Gesundheitsholding GmbH
Neurology, Sierninger Straße 170, 4400, Steyr

Germany

39 sites · Ended
Medicross MVZ GmbH
MediCross MVZ, Bahnhofplatz 4, 74172, Neckarsulm
Westmecklenburg Klinikum Helene von Buelow GmbH
Center for Pain and Back Therapy, Parkstraße 12, 19230, Hagenow
Schmerztherapiezentrum Brau Michel
Center for Pain Therapy, Julius-Heywinkel-Weg 1, Westerberg, Osnabrück
Katholisches Klinikum Bochum gGmbH
Center for Sexual Health and Medicine, Bleichstrasse 15, Innenstadt, Bochum
BDH-Klinik Elzach gGmbH
Neurological Early Rehabilitation, Am Tannwald 1-3, 79215, Elzach
Universitaetsklinikum Essen AöR
Clinic for Neurology, Hufelandstrasse 55, Holsterhausen, Essen
Universitatsklinikum Wurzburg AöR
Orthopedic Department of the University Hospital Würzburg, Brettreichstraße 11, Frauenland, Würzburg
BG Klinikum Unfallkrankenhaus Berlin gGmbH
Clinic for Anesthesiology, Intensive Care and Pain Medicine, Warener Strasse 7, Biesdorf, Berlin
Gemeinschaftspraxis Michael Jokiel und Andreas Lütgen
Joint Practice, Facharztzentrum I am Krankenhaus, Propst-Sievert-Weg 8, Borken
Schmerzzentrum Bocholt
Center for Pain Therapy, Kreuzstrasse 15, Stadt, Bocholt
Schmerzzentrum Inn-Salzach
Center for Pain Therapy, Wackerstrasse 7, 84489, Burghausen
Hausarztzentrum Butendorf
Medical Practice, Horster Strasse 137, Butendorf, Gladbeck
BG Klinikum Hamburg gGmbH
Pain Medicine, Bergedorfer Strasse 10, Lohbruegge, Hamburg
Praxisklinik Dr. Ibrahim & Kollegen
Pain center and practice clinic, Willy-Brandt-Platz 5, 81829, München
Christliches Klinikum Unna gGmbH
Clinic for Anesthesiology, Intensive Care, Emergency, Pain and Palliative Medicine, Obere Husemannstrasse 2, 59423, Unna
Ruhr University
St. Josef Hospital, Clinic for Neurology, Gudrunstrasse 56, Grumme, Bochum
University Medical Centre Schleswig-Holstein
Clinic for Anesthesiology and Surgical Intensive Care Medicine, Schwanenweg 21, Arnold-Heller-Straße 3, Brunswik, Kiel
Universitaetsklinikum Tuebingen
Clinic for Anesthesiology and Intensive Care Medicine, Hoppe-Seyler-Strasse 3, Nordstadt, Tuebingen
Charite Universitatsmedizin Berlin KöR
Clinic for Anesthesiology with Focus on Surgical Intensive Care Medicine, Hindenburgdamm 30, Lichterfelde, Berlin
Universitaetsklinikum Giessen und Marburg GmbH
Clinic for Anesthesia and Intensive Therapy, Baldingerstrasse 1, 35043, Marburg
Klinikum Dortmund gGmbH
Clinic for Neurology, Münsterstraße 240, Mitte, Dortmund
Schmerztherapiezentrum Villingen-Schwenningen
Center for Pain Therapy, Albert-Schweitzer-Str. 6, 78052, Villingen-Schwenningen
Zentrum für Schmerz- und Palliativmedizin Schwerte
Center for Pain and Palliative Medicine, Große Marktstr. 5, 58239, Schwerte
University of Leipzig
Clinic and Polyclinic for Anesthesiology and Intensive Care Therapy, Liebigstrasse 20, Zentrum-Suedost, Leipzig
Klinikum rechts der Isar der TU Muenchen AöR
Clinic and Polyclinic for Neurology, Ismaninger Straße 22, Au-Haidhausen, Munich
Schwerpunktpraxis Fuer Schmerztherapie Berufsausübungsgemeinschaft GbR
Specialized Practice for Pain Therapy, Bahnhofstraße 13, Mitte, Ulm
BG Klinik Tübingen
Pain Medicine, Schnarrenbergstrasse 95, 72076, Tübingen
Universitatsmedizin der Johannes Gutenberg-Universitat Mainz KöR
Clinic for Anesthesiology, Langenbeckstraße 1, Oberstadt, Mainz
Saarland University Hospital
Center for Cross-age Palliative Care and Pediatric Pain Therapy, Gebaeude 52 57, Kirrberger Strasse 100, Homburg
Universitaetsklinikum Essen AöR
Clinic for Neurology, Hufelandstrasse 55, Holsterhausen, Essen
Algesiologikum MVZ GmbH
Algesiologikum MVZ, Heßstraße 22, Maxvorstadt, Munich
BG Klinikum Duisburg gGmbH
Pain Medicine, Grossenbaumer Allee 250, Buchholz, Duisburg
University Hospital Augsburg
Clinic for Anesthesiology and Surgical Intensive Care Medicine, Stenglinstrasse 2, Kriegshaber, Augsburg
Staedtisches Klinikum Karlsruhe gGmbH
Center for Pain Therapy, Moltkestraße 90, Weststadt, Karlsruhe
Ueberoertliche Berufsausuebungsgemeinschaft Schmerz Und Palliativzentrum Rhein Main GbR
Center for Pain Therapy and Palliative Care, Broennerstrasse 15, Innenstadt, Frankfurt Am Main
Marien Hospital Herne Universitatsklinikum Der Ruhr-Universitat Bochum
Clinic for Anesthesiology, Surgical Intensive Care, Pain and Palliative Medicine, Hoelkeskampring 40, Herne-Sued, Herne
Berufsgenossenschaftliches Universitaetsklinikum Bergmannsheil gGmbH
Neurology, Buerkle De La Camp-Platz 1, Wiemelhausen, Bochum
Schmerzzentrum Geldern
Praxis, An der Insel 15, 47608, Geldern
Universitätsklinikum Frankfurt
Clinic for Anesthesiology, Theodor-Stern-Kai 7, 60590, Frankfurt

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country Trial startTrial end Recruitment startRecruitment end Early termination
Austria 2023-12-04 2024-01-09 2025-01-28
Germany 2023-11-02 2023-11-14 2025-01-28

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 2 · Art. 38 CTR

Temporary halt TH-70155

Halt date
2025-01-28
Member states concerned
Germany
Publication date
2025-02-10
Reason
Study management related
Explanation
The recruitment for the clinical trial was halted due to a request of the competent authority based on findings in an inspection according to that personal data of the participants are accessible to the sponsor. Additionally, concerns about the current level of monitoring, especially the low level of on-site monitoring, and its documentation being not adequate to ensure that the rights, safety and well-being of participants are protected. A modification of inadequate procedures is requested to meet all responsibilities of the sponsors and the sites.
Follow-up measures
First measures to correct the accessibility of personal data have already been implemented on 11.11.2024. The level of on-site monitoring activities has been increased steadily and will continue based on an updated monitoring plan. Additionally, a detailed CAPA will be initiated based on inspection findings and extended measures will be implemented.
Due to the implemented changes, enrolled participants are already provided with extensive measures, both protecting their personal data and ensuring their rights, safety and well-being. Their required procedures as well as the supply with the investigational product required in the clinical trial are ensured together with an improved oversight through the sponsor.
Benefit-risk balance changed
No
Treatment stopped
No

Temporary halt TH-70153

Halt date
2025-01-28
Member states concerned
Austria
Publication date
2025-02-10
Reason
Study management related
Explanation
The recruitment for the clinical trial was halted due to a request of the competent authority based on findings in an inspection according to that personal data of the participants are accessible to the sponsor. Additionally, concerns about the current level of monitoring, especially the low level of on-site monitoring, and its documentation being not adequate to ensure that the rights, safety and well-being of participants are protected. A modification of inadequate procedures is requested to meet all responsibilities of the sponsors and the sites.
Follow-up measures
First measures to correct the accessibility of personal data have already been implemented on 11.11.2024. The level of on-site monitoring activities has been increased steadily and will continue based on an updated monitoring plan. Additionally, a detailed CAPA will be initiated based on inspection findings and extended measures will be implemented.
Due to the implemented changes, enrolled participants are already provided with extensive measures, both protecting their personal data and ensuring their rights, safety and well-being. Their required procedures as well as the supply with the investigational product required in the clinical trial are ensured together with an improved oversight through the sponsor.
Benefit-risk balance changed
No
Treatment stopped
No

Corrective measures 1 · Art. 77 CTR

Corrective measure CM-DE-0001

Member state
Germany
Publication date
2025-02-07
Type
4
Reason
4
Immediate action required
No
Justification
A clinical trial may be conducted only where the anticipated benefits to the subjects or to public health justify the foreseeable risks and inconveniences and compliance with this condition is constantly monitored (Regulation (EU) 536/2014, Art. 28 (1) (a)). The sponsor of a clinical trial and the investigator shall ensure that the clinical trial is conducted in accordance with the protocol and with the principles of good clinical practice (Regulation (EU) 536/2014, Art. 47). In view of the latest inspection findings, there are justified grounds for considering that these requirements are not met. The member states concerned intend to suspend the clinical trial (Regulation (EU) 536/2014, art. 77 (1) (b)). The sponsor is requested to deliver its opinion on this (Regulation (EU) 536/2014, art. 77 (2)).

Application history

6 submissions — initial application plus substantial / non-substantial modifications

#TypeCodeSubmittedReference MSConclusionDecision date
1 INITIAL IN 2022-11-28 Germany Acceptable
2023-04-03
 2023-04-06
2 SUBSTANTIAL MODIFICATION SM-1 2023-05-12 Germany Acceptable 2023-06-20
3 SUBSTANTIAL MODIFICATION SM-5 2023-05-12 Acceptable 2023-08-03
4 SUBSTANTIAL MODIFICATION SM-6 2023-08-21 Germany Acceptable
2023-10-23
 2023-10-24
5 SUBSTANTIAL MODIFICATION SM-8 2023-12-19 Germany Acceptable
2024-02-19
 2024-02-20
6 SUBSTANTIAL MODIFICATION SM-12 2024-06-12 Germany Acceptable 2024-07-01

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