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Tolerability and Analgesic Efficacy of Loxapine in Patients With Refractory, Chemotherapy-induced Neuropathic Pain (LOX2015PILOT)

Primary Purpose

Neuropathic Pain

Status
Terminated
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Loxapine
Sponsored by
University of Witten/Herdecke
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuropathic Pain focused on measuring Neuropathic pain, Loxapine, Antipsychotics, Co-Analgesics, Tolerability, Analgesic efficacy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Primarily chemotherapy-induced neuropathic pain (including mixed pain) for at least 3 months refractory to at least one analgesic compound
  • Neuropathic pain >= 4 (11-point numeric pain scale) at screening visit (including mixed pain)
  • Age >= 18 years
  • Body weight between 50 and 150 kg
  • Given written informed consent

Exclusion Criteria:

  • Participation in other interventional clinical studies (currently or within the last 3 months)
  • Parkinson's disease, movement disorders (extrapyramidal signs and symptoms) associated with antipsychotics, neuroleptic malignant syndrome, other syndromes associated with antipsychotics
  • Severe hypotension with a syncope in history, glaucoma, urinary retention, epilepsy or other seizure disorders in history, severe dementia, dementia-related psychosis in history, malignancies with a life expectancy of less than 6 months, breast cancer in history, other life-threatening conditions
  • Corrected QT interval (QTc) > 460 ms (females) or > 450 ms (males)
  • Known alcohol and/or drug abuse
  • Concomitant intake of antipsychotics, dopamine agonists (Levodopa, bromocriptine, lisuride, pergolide, ropinirole, cabergoline, pramipexole, apomorphine), alpha-receptor blocking compounds
  • Compounds with a strong evidence for a clinically relevant QT interval prolongation or torsade de pointes risk increase
  • Strong inhibitors of CYP1A2, CYP2D6, or CYP3A4
  • Known CYP2D6 Poor metabolizer status
  • Pregnancy or lactation period
  • Missing or insufficient contraception in pre- or perimenopausal women
  • Close Affiliation with the investigational site

Sites / Locations

  • HELIOS Clinic Wuppertal

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Loxapine

Arm Description

Loxapine Capsules 10 mg Day 1- 14: 10 mg b.i.d Day 15-28: 10 mg t.i.d Day 29-42: 20 mg b.i.d. Day 43-56: 20 mg t.i.d. Dosages will be escalated according to analgesic efficacy and tolerability.

Outcomes

Primary Outcome Measures

Loxapine dosage with the lowest incidence of events.
The primary endpoint is defined as the first occurrence of a (serious) adverse event ((S)AE) leading to dose reduction or withdrawal of loxapine ("event"). The loxapine dosage with the lowest incidence of events will be identified.

Secondary Outcome Measures

Number, type, and severity of (serious) adverse events ((S)AEs)
Number, type, and severity of (serious) adverse events ((S)AEs)
Cumulative incidence rates for (S)AE pattern of study participants
Cumulative incidence rates for (S)AE pattern of study participants
Individual (study participant-related) incidence of individual (S)AEs
Individual (study participant-related) incidence of individual (S)AEs
Individual (study participant-related) changes in pain severity (NRS scale)
Individual (study participant-related) changes in pain severity (measured by using 11-point numeric pain rating scale) in relation to treatment phase and loxapine dosage
Association between event pattern and individual pain level (NRS scale)
Assessment of the association between the pattern of events (Primary endpoint) related to the individual pain level (clinically relevant pain reduction is defined by an at least 30% decrease or an absolute decrease of two scale units compared to baseline using 11-point numeric pain rating scale.
Individual (study participant-related) changes in pain severity (painDETECT)
Individual (study participant-related) changes in pain severity (measured by painDETECT questionnaire) in relation to treatment phase and loxapine dosage
Association between event pattern and individual pain level (painDETECT)
Assessment of the association between the pattern of events (Primary endpoint) related to the individual changes in pain severity / characteristics measured by painDETECT questionnaire
Individual (study participant-related) changes in QoL (SF-12v2)
Individual (study participant-related) changes in the quality of life (12-item Short Form Health Survey (SF-12v2)) in relation to treatment phase and loxapine dosage
Association between event pattern and QoL (SF-12v2)
Assessment of the association between the pattern of events (Primary endpoint) related to the individual quality of life changes changes (12-item Short Form Health Survey (SF-12v2))
Individual (study participant-related) changes in anxiety and depression (HADS-D scale)
Individual (study participant-related) changes in anxiety and depression (HADS-D scale) in relation to treatment phase and loxapine dosage
Association between event pattern and anxiety and depression (HADS-D scale)
Assessment of the association between the pattern of events (Primary endpoint) related to the individual changes in anxiety and depression (HADS-D scale)
Association between event pattern and analgesic co-medication
Assessment of the association between the pattern of events (Primary endpoint) related to the individual changes in analgesic co-medication

Full Information

First Posted
June 14, 2016
Last Updated
June 30, 2022
Sponsor
University of Witten/Herdecke
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1. Study Identification

Unique Protocol Identification Number
NCT02820519
Brief Title
Tolerability and Analgesic Efficacy of Loxapine in Patients With Refractory, Chemotherapy-induced Neuropathic Pain
Acronym
LOX2015PILOT
Official Title
Tolerability and Analgesic Efficacy of Loxapine in Patients With Refractory, Chemotherapy-induced Neuropathic Pain
Study Type
Interventional

2. Study Status

Record Verification Date
August 2017
Overall Recruitment Status
Terminated
Why Stopped
Intolerable high amount of adverse events
Study Start Date
June 7, 2016 (undefined)
Primary Completion Date
May 4, 2017 (Actual)
Study Completion Date
May 4, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Witten/Herdecke

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Loxapine is an antipsychotic drug approved for the treatment of schizophrenia in several countries including the United States. In animal studies in mice, loxapine reduced neuropathic pain. Hence, in a proof-of-principle and dose-escalating study the tolerability and analgesic efficacy of loxapine will be evaluated in patients with neuropathic pain.
Detailed Description
In this dose-escalating study, 12 patients with refractory, chemotherapy-induced neuropathic pain (including mixed pain) will receive loxapine during four 14-days treatment episodes. The dosage for episode 1 (Days 1-14) will be 10 mg b.i.d., dosages for episodes 2, 3, and 4 will be defined by taking into account tolerability and analgesic efficacy of the former episode. In case of an acceptable tolerability and if a clinically relevant analgesic efficacy is not reached, loxapine dosage will be increased (2nd Episode 10 mg t.i.d, 3rd Episode 20 mg b.i.d., 4th episode 20 mg t.i.d.). In case of an acceptable tolerability and if a clinically relevant analgesic efficacy is reached, loxapine dosage will not be changed. If clinically relevant (serious) adverse events ((S)AEs) occur, loxapine dosage will be reduced or the treatment will be interrupted or stopped irrespective of the analgesic efficacy. A clinically relevant pain reduction / analgesic efficacy is defined by an at least 30% decrease or an absolute decrease of two scale units compared to baseline using 11-point numeric pain rating scale. Patients will receive loxapine as add-on treatment to their usual (analgesic) care.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuropathic Pain
Keywords
Neuropathic pain, Loxapine, Antipsychotics, Co-Analgesics, Tolerability, Analgesic efficacy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
4 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Loxapine
Arm Type
Experimental
Arm Description
Loxapine Capsules 10 mg Day 1- 14: 10 mg b.i.d Day 15-28: 10 mg t.i.d Day 29-42: 20 mg b.i.d. Day 43-56: 20 mg t.i.d. Dosages will be escalated according to analgesic efficacy and tolerability.
Intervention Type
Drug
Intervention Name(s)
Loxapine
Other Intervention Name(s)
Loxapine Succinate
Intervention Description
Loxapine dose escalation according to tolerability and analgesic efficacy
Primary Outcome Measure Information:
Title
Loxapine dosage with the lowest incidence of events.
Description
The primary endpoint is defined as the first occurrence of a (serious) adverse event ((S)AE) leading to dose reduction or withdrawal of loxapine ("event"). The loxapine dosage with the lowest incidence of events will be identified.
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Secondary Outcome Measure Information:
Title
Number, type, and severity of (serious) adverse events ((S)AEs)
Description
Number, type, and severity of (serious) adverse events ((S)AEs)
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Cumulative incidence rates for (S)AE pattern of study participants
Description
Cumulative incidence rates for (S)AE pattern of study participants
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Individual (study participant-related) incidence of individual (S)AEs
Description
Individual (study participant-related) incidence of individual (S)AEs
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Individual (study participant-related) changes in pain severity (NRS scale)
Description
Individual (study participant-related) changes in pain severity (measured by using 11-point numeric pain rating scale) in relation to treatment phase and loxapine dosage
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Association between event pattern and individual pain level (NRS scale)
Description
Assessment of the association between the pattern of events (Primary endpoint) related to the individual pain level (clinically relevant pain reduction is defined by an at least 30% decrease or an absolute decrease of two scale units compared to baseline using 11-point numeric pain rating scale.
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Individual (study participant-related) changes in pain severity (painDETECT)
Description
Individual (study participant-related) changes in pain severity (measured by painDETECT questionnaire) in relation to treatment phase and loxapine dosage
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Association between event pattern and individual pain level (painDETECT)
Description
Assessment of the association between the pattern of events (Primary endpoint) related to the individual changes in pain severity / characteristics measured by painDETECT questionnaire
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Individual (study participant-related) changes in QoL (SF-12v2)
Description
Individual (study participant-related) changes in the quality of life (12-item Short Form Health Survey (SF-12v2)) in relation to treatment phase and loxapine dosage
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Association between event pattern and QoL (SF-12v2)
Description
Assessment of the association between the pattern of events (Primary endpoint) related to the individual quality of life changes changes (12-item Short Form Health Survey (SF-12v2))
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Individual (study participant-related) changes in anxiety and depression (HADS-D scale)
Description
Individual (study participant-related) changes in anxiety and depression (HADS-D scale) in relation to treatment phase and loxapine dosage
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Association between event pattern and anxiety and depression (HADS-D scale)
Description
Assessment of the association between the pattern of events (Primary endpoint) related to the individual changes in anxiety and depression (HADS-D scale)
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)
Title
Association between event pattern and analgesic co-medication
Description
Assessment of the association between the pattern of events (Primary endpoint) related to the individual changes in analgesic co-medication
Time Frame
After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Primarily chemotherapy-induced neuropathic pain (including mixed pain) for at least 3 months refractory to at least one analgesic compound Neuropathic pain >= 4 (11-point numeric pain scale) at screening visit (including mixed pain) Age >= 18 years Body weight between 50 and 150 kg Given written informed consent Exclusion Criteria: Participation in other interventional clinical studies (currently or within the last 3 months) Parkinson's disease, movement disorders (extrapyramidal signs and symptoms) associated with antipsychotics, neuroleptic malignant syndrome, other syndromes associated with antipsychotics Severe hypotension with a syncope in history, glaucoma, urinary retention, epilepsy or other seizure disorders in history, severe dementia, dementia-related psychosis in history, malignancies with a life expectancy of less than 6 months, breast cancer in history, other life-threatening conditions Corrected QT interval (QTc) > 460 ms (females) or > 450 ms (males) Known alcohol and/or drug abuse Concomitant intake of antipsychotics, dopamine agonists (Levodopa, bromocriptine, lisuride, pergolide, ropinirole, cabergoline, pramipexole, apomorphine), alpha-receptor blocking compounds Compounds with a strong evidence for a clinically relevant QT interval prolongation or torsade de pointes risk increase Strong inhibitors of CYP1A2, CYP2D6, or CYP3A4 Known CYP2D6 Poor metabolizer status Pregnancy or lactation period Missing or insufficient contraception in pre- or perimenopausal women Close Affiliation with the investigational site
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sven Schmiedl, MD
Organizational Affiliation
Witten/Herdecke University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Sven Schmiedl, MD
Organizational Affiliation
HELIOS Clinic Wuppertal
Official's Role
Principal Investigator
Facility Information:
Facility Name
HELIOS Clinic Wuppertal
City
Wuppertal
State/Province
NRW
ZIP/Postal Code
42283
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31402867
Citation
Schmiedl S, Peters D, Schmalz O, Mielke A, Rossmanith T, Diop S, Piefke M, Thurmann P, Schmidtko A. Loxapine for Treatment of Patients With Refractory, Chemotherapy-Induced Neuropathic Pain: A Prematurely Terminated Pilot Study Showing Efficacy But Limited Tolerability. Front Pharmacol. 2019 Jul 25;10:838. doi: 10.3389/fphar.2019.00838. eCollection 2019.
Results Reference
derived

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Tolerability and Analgesic Efficacy of Loxapine in Patients With Refractory, Chemotherapy-induced Neuropathic Pain

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