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

Study Overview
=================
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.

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

Conditions
-----------------
Neuropathic Pain

Intervention / Treatment
-----------------
* Drug: Loxapine


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Loxapine<br>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. | Drug: Loxapine<br>* Loxapine dose escalation according to tolerability and analgesic efficacy<br>* Other names: Loxapine Succinate;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number, type, and severity of (serious) adverse events ((S)AEs) | Number, type, and severity of (serious) adverse events ((S)AEs) | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| Cumulative incidence rates for (S)AE pattern of study participants | Cumulative incidence rates for (S)AE pattern of study participants | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| Individual (study participant-related) incidence of individual (S)AEs | Individual (study participant-related) incidence of individual (S)AEs | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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 | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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. | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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 | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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 | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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 | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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)) | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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 | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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) | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 
| 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 | After each of the four 14 days study episodes (Day 15, Day 29, Day 43, Day 57) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neuropathic pain, Loxapine, Antipsychotics, Co-Analgesics, Tolerability, Analgesic efficacy