A Norwegian Trial Comparing Treatment Strategies for Carpal Tunnel Syndrome

Study Overview
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Brief Summary
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Carpal tunnel syndrome (CTS) causes numbness and pain in the hand and arm, and is an important cause of work absence and disability. The aim of the NOR-CACTUS Trial is to compare outcomes of a treatment strategy where the initial treatment is up to two ultrasound-guided corticosteroid injections, followed by scheduled clinical assessment of treatment effect, and subsequent surgery if needed, to a treatment strategy where surgery is the first-line treatment. Participants will be randomized to one of the treatment strategies, and followed up for two years after start of the study intervention. Outcomes will include patient-reported, clinical, functional and neurophysiological measures, and health-economic aspects. The hypothesis of the study is that there is no difference between the two treatment groups in the percentage of patients with a satisfactory symptom relief (treatment success) one year after the initial therapeutic intervention.

Detailed Description
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CTS is the most common non-traumatic hand disorder, prevalent in approximately 4% of the adult population. The condition may have a substantial impact on an individual's quality of life, ability to accomplish activities of daily living, and to perform occupational duties. Associated healthcare costs represent a significant socioeconomic burden. Currently, many patients with mild and moderate CTS treated surgically without a preceding trial of less invasive non-surgical therapies. An increase in the use of non-surgical first-line therapies (e.g. corticosteroid injection into the carpal tunnel), while reserving surgery for refractory cases, aim to optimize the trade-off between treatment risk and benefit, while also ensuring appropriate use of health resources. However, there is a lack of studies directly comparing the efficacy of corticosteroid injections to surgery, and the long-term safety of corticosteroid injections has not been investigated. It is not well-known if patients who are initially treated with corticosteroid injections will eventually need to proceed to surgery, and therefore may have to endure the symptoms for a longer period of time, with potentially worse long-term outcomes, compared to patients who has surgery as first-line treatment. On the other hand, it is not beneficial if patients are unnecessarily exposed to the risks associated with surgery, if symptoms could have been satisfactory resolved with a non-surgical method. The current study will assess if first-line treatment with up to two ultrasound-guided corticosteroid injections is non-inferior to surgery with regards to treatment success. A less invasive treatment approach might result in important benefits to the patient, e.g. less pain, reduced risk of complications, and faster return to work and activities. This might also be of importance to family members, as many CTS patients are at an age where they have care responsibilities. Non-surgical treatments might benefit society by decreasing work absence and reducing health expenditure, and allowing better access to surgical services for other patient groups. High quality documentation is needed to provide a base for future treatment guidelines. Evidence based clinical guidelines provide treatment decision support and help reduce national and regional differences in treatment practices, and ensure that all patients have equal access to evidence-based treatment. In the NOR-CACTUS trial, adult individuals with idiopathic CTS of a mild-to-moderate degree will be randomized to receive either A) Primary open surgical carpal tunnel release, or B) Up to two ultrasound-guided corticosteroid (triamcinolone hexacetonide) injections in the carpal tunnel, and subsequent open surgical carpal tunnel release in case of unsatisfactory treatment result. Participants will be randomized to receive one of the treatment strategies, and followed for two years, with the primary endpoint being successful treatment result one year after start of the intervention. The hypothesis of the study is that the percentage of patients with a satisfactory symptom relief (treatment success) one year after the initial therapeutic intervention in the injection treatment strategy arm is non-inferior to that of the surgery treatment arm. The primary outcome is based on the disease-specific patient-reported outcome Boston Carpal Tunnel Questionnaire (BCTQ) symptom severity scale (SSS). Further outcomes will include other patient-reported, clinical, functional and neurophysiological measures, and health-economic aspects.

Official Title
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The NOR-CACTUS Trial - A Norwegian Trial Comparing Treatment Strategies for Carpal Tunnel Syndrome

Conditions
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Carpal Tunnel Syndrome

Intervention / Treatment
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* Procedure: Surgical carpal tunnel release
* Drug: Injection, Triamcinolone Hexacetonide, Per 5 Mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥18 years of age) Patient history indicating CTS Neurophysiological examination performed within 6 months Diagnosis of CTS based on: Classic/probable or possible symptoms, and neurophysiological findings consistent with CTS Or, in case of normal neurophysiological findings: Classic/probable symptoms and positive physical exam findings and/or nighttime symptoms Mild to moderate symptoms (intermittent, interfering with everyday life, and/or disturb sleep) Exclusion Criteria: Previous CTS surgery or corticosteroid injection in the carpal tunnel in the relevant hand Diagnosis of severe CTS, based on history and examination indicating severe CTS with constant symptoms including pain, loss of sensibility, dexterity or reduced temperature sensation, weakness of thumb abduction and opposition, or atrophy of thenar musculature. Disappearance of pain may indicate permanent sensory loss. History suggesting underlying causes of CTS e.g. inflammatory wrist arthritis and/or flexor tenosynovitis Previous significant trauma or fracture, deformity or tumor in the wrist or hand in the relevant hand Presence of conditions affecting a normal nerve function e.g. cervical disc herniation, polyneuropathy or previous nerve injury Major co-morbidities, such as severe malignancies, severe or uncontrolled infections, uncontrollable hypertension, severe cardiovascular disease (NYHA class III or IV) and/or severe respiratory diseases, severe renal failure, active ulcus ventriculi, leukopenia and/or thrombocytopenia Severe psychiatric or mental disorders Local infection or wound in the affected hand/wrist Any other medical condition that according to the treating physician and/or local guidelines makes adherence to treatment protocol impossible Inadequate birth control1, pregnancy2, and/or breastfeeding (current at screening or planned within the duration of the study) Known hypersensitivity to Triamcinolone Hexacetonide (Lederspan) or any of the excipients (sorbitol, polysorbate or benzyl alcohol) Concomitant therapy with CYP3A-inhibitors or digitalis glycosides Patients vaccinated or immunized with live virus vaccines within 2 weeks of treatment Alcohol or other substance abuse Language barriers Other factors which make adherence to study protocol impossible

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two-arm, prospective, multi-center, parallel-group, open-label assessor-blinded non-inferiority treatment strategy study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Surgery treatment strategy<br>Primary open surgical carpal tunnel release. Treatment effect is monitored on scheduled follow-up visits. Re-operation may be performed if medically indicated (e.g. postoperative complication, or failure of the primary procedure) | Procedure: Surgical carpal tunnel release<br>* Open surgical division of the flexor retinaculum of the palm/wrist to release pressure on the median nerve<br>* Other names: Open surgical carpal tunnel release;|
| Experimental: Injection treatment strategy<br>Primary treatment with ultrasound-guided corticosteroid injection. Treatment effect is monitored on scheduled follow-up visits. One additional injection may be administered, and subsequently surgical carpal tunnel release is performed in case of unsatisfactory treatment effect of the injection therapy. Treatment effect is graded on a 5-leve scale by subject from 1 (complete improvement) to 5 (severe worsening) of symptoms. Incomplete improvement (score 2 or higher) results in a second injection or secondary surgery. | Procedure: Surgical carpal tunnel release<br>* Open surgical division of the flexor retinaculum of the palm/wrist to release pressure on the median nerve<br>* Other names: Open surgical carpal tunnel release;Drug: Injection, Triamcinolone Hexacetonide, Per 5 Mg<br>* Ultrasound-guided injection of 20 mg of triamcinolone hexacetonide (or -acetonide) into the carpal tunnel space close to the median nerve<br>* Other names: Ultrasound-guided corticosteroid injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful treatment result after 12 months | Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5 after 12 months Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ SSS, Levine et. al 1993) is a disease-specific patient-reported outcome for CTS-related symptom severity. 11 items are scored by the patient on an ordinal scale from 1 (best) to 5 (worst), providing a mean score ranged 1-5. The primary outcome measure is achievement of BCTQ SSS ≤ 1.5, interpreted as a successful treatment result, 12 months after start of the study intervention. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful treatment result after 3 months | Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5 after 3 months Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ SSS, Levine et. al 1993) is a disease-specific patient-reported outcome for CTS-related symptom severity. 11 items are scored by the patient on an ordinal scale from 1 (best) to 5 (worst), providing a mean score ranged 1-5. The outcome measure is achievement of BCTQ SSS ≤ 1.5, interpreted as a successful treatment result, 3 months after start of the study intervention. | 3 months | 
| Successful treatment result after 6 months | Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5 after 6 months Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ SSS, Levine et. al 1993) is a disease-specific patient-reported outcome for CTS-related symptom severity. 11 items are scored by the patient on an ordinal scale from 1 (best) to 5 (worst), providing a mean score ranged 1-5. The outcome measure is achievement of BCTQ SSS ≤ 1.5, interpreted as a successful treatment result, 6 months after start of the study intervention. | 6 months | 
| Successful treatment result after 24 months | Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5 after 24 months Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ SSS, Levine et. al 1993) is a disease-specific patient-reported outcome for CTS-related symptom severity. 11 items are scored by the patient on an ordinal scale from 1 (best) to 5 (worst), providing a mean score ranged 1-5. The outcome measure is achievement of BCTQ SSS ≤ 1.5, interpreted as a successful treatment result, 24 months after start of the study intervention. | 24 months | 
| Boston Carpal Tunnel Questionnaire Symptom Severity Scale | Boston Carpal Tunnel Questionnaire Symptom Severity Scale (range 1-5) Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ SSS, Levine et. al 1993) is a disease-specific patient-reported outcome for CTS-related symptom severity. 11 items are scored by the patient on an ordinal scale from 1 (best) to 5 (worst), providing a mean score ranged 1-5, used as outcome measure. | 0-24 months | 
| Boston Carpal Tunnel Questionnaire Functional Status Scale | Boston Carpal Tunnel Questionnaire Functional Status Scale (range 1-5) Boston Carpal Tunnel Questionnaire Functional Status Scale (BCTQ FSS, Levine et. al 1993) is a disease-specific patient-reported outcome for CTS-related functional impairment. 11 items are scored by the patient on an ordinal scale from 1 (best) to 5 (worst), providing a mean score ranged 1-5, used as outcome measure. | 0-24 months | 
| Nerve conduction studies: Motor median nerve distal latency | Nerve conduction studies of motor median nerve distal latency (milliseconds) Measurement points: Distal: at the wrist, 8 cm proximal to the m. abductor pollicis brevis. Proximal: at the cubital fossa | 0 and 12 months | 
| Nerve conduction studies: Motor median nerve proximal latency | Nerve conduction studies of motor median nerve proximal latency (milliseconds) Median nerve measurement points: Distal: at the wrist, 8 cm proximal to the m. abductor pollicis brevis. Proximal: at the cubital fossa | 0 and 12 months | 
| Nerve conduction studies: Motor median nerve amplitude | Nerve conduction studies of motor median nerve amplitude (millivolts) Median nerve measurement points: Distal: at the wrist, 8 cm proximal to the m. abductor pollicis brevis. Proximal: at the cubital fossa | 0 and 12 months | 
| Nerve conduction studies: Motor median nerve conduction velocity | Nerve conduction studies of motor median nerve amplitude conduction velocity (meters per second) Median nerve measurement points: Distal: at the wrist, 8 cm proximal to the m. abductor pollicis brevis. Proximal: at the cubital fossa | 0 and 12 months | 
| Nerve conduction studies: Motor ulnar nerve distal latency | Nerve conduction studies of motor ulnar nerve distal latency (milliseconds) Ulnar nerve measurement points: Distal: at the wrist, 8 cm proximal to the abductor digiti minimi Proximal: 3 cm distal to the medial epicondyle of the elbow | 0 and 12 months | 
| Nerve conduction studies: Motor ulnar nerve proximal latency | Nerve conduction studies of motor ulnar nerve proximal latency (milliseconds) Ulnar nerve measurement points: Distal: at the wrist, 8 cm proximal to the abductor digiti minimi Proximal: 3 cm distal to the medial epicondyle of the elbow | 0 and 12 months | 
| Nerve conduction studies: Motor ulnar nerve amplitude | Nerve conduction studies of motor ulnar nerve amplitude (millivolts) Ulnar nerve measurement points: Distal: at the wrist, 8 cm proximal to the abductor digiti minimi Proximal: 3 cm distal to the medial epicondyle of the elbow | 0 and 12 months | 
| Nerve conduction studies: Motor ulnar nerve conduction velocity | Nerve conduction studies of motor ulnar nerve conduction velocity (meters per second) Ulnar nerve measurement points: Distal: at the wrist, 8 cm proximal to the abductor digiti minimi Proximal: 3 cm distal to the medial epicondyle of the elbow | 0 and 12 months | 
| Nerve conduction studies: Sensory median nerve latency | Nerve conduction studies of sensory median nerve latency (milliseconds) Median nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance | 0 and 12 months | 
| Nerve conduction studies: Sensory median nerve amplitude | Nerve conduction studies of sensory median nerve amplitude (microvolts) Median nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance | 0 and 12 months | 
| Nerve conduction studies: Sensory median nerve conduction velocity | Nerve conduction studies of sensory median nerve conduction velocity (meters per second) Median nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance | 0 and 12 months | 
| Nerve conduction studies: Sensory ulnar nerve latency | Nerve conduction studies of sensory ulnar nerve latency (milliseconds) Ulnar nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance | 0 and 12 months | 
| Nerve conduction studies: Sensory ulnar nerve amplitude | Nerve conduction studies of sensory ulnar nerve amplitude (microvolts) Ulnar nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance | 0 and 12 months | 
| Nerve conduction studies: Sensory ulnar nerve conduction velocity | Nerve conduction studies of sensory ulnar nerve conduction velocity (meters per second) Ulnar nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance | 0 and 12 months | 
| Electromyography: Spontaneous activity | Electromyography recording spontaneous activity in m.abductor pollicis brevis (Yes/No) | 0 and 12 months | 
| Electromyography: Chronic neurogenic changes | Electromyography recording chronic neurogenic changes in m.abductor pollicis brevis (Yes/No) | 0 and 12 months | 
| Nerve conduction studies: Bland score | Scoring of motor and sensory nerve conduction studies using the Bland scoring system (Bland, et al. 2000): 0: normal 1: very mild 2: mild 3: moderate 4: severe 5: very severe 6: extremely severe 7: not gradable | 0 and 12 months | 
| Semmes-Weinstein monofilament test | Bilateral test of sensory function in digits 1,2 and 5 using a 2.83 monofilament. Graded absent/present. | 0-24 months | 
| Grip strength | Test of grip strength using dynamometer. Range 0-90 kg. | 0-24 months | 
| Grip ability test (GAT) | Simplified version of the Sollerman grip function test. Measures time for subject to perform 3 tasks: Pulling a tubular bandage over the hand, putting a paper clip on an envelope, and pouring water from a jar into a cup. Range 0-60 seconds for each task. Outcome measure is calculated as: tubular bandage (seconds) x 1.8 + paper clip on an envelope (seconds) + pouring water (seconds) x 1.8 | 0-24 months | 
| Patient assessment of treatment effect on symptoms | Patient-reported assessment of treatment effect on symptoms (current state compared to before treatment), reported on a 5-level ordinal (Likert) scale from 1 (best) to 5 (worst). | 3-24 months | 
| Patient assessment of expected treatment effect on symptoms | Patient-reported expectation (reported by the patient prior to treatment) of the treatment's effect on symptoms, reported on a 5-level ordinal (Likert) scale from 1 (best) to 5 (worst). | 0 months | 
| Patient assessment of CTS symptoms | Patient-reported assessment of CTS-related symptoms (current state), reported on a 5-level ordinal (Likert) scale from 1 (best) to 5 (worst). | 0-24 months | 
| Patient assessment of CTS-related functional impairment | Patient-reported assessment of current CTS-related functional impairment (current state), reported on a 5-level ordinal (Likert) scale from 1 (best) to 5 (worst). | 0-24 months | 
| Patient assessment of acceptability of CTS-related symptoms and functional disability | Patient assessment if the current CTS-related symptoms and functional disability are acceptable (yes or no) | 0-24 months | 
| Ultrasound measure of proximal cross-sectional area of the median nerve | Bilateral evaluation of the proximal cross-sectional area of the median nerve (square millimeters) (as specified in protocol) | 0-24 months | 
| Ultrasound measure of distal cross-sectional area of the median nerve | Bilateral evaluation of the distal cross-sectional area of the median nerve (square millimeters) (as specified in protocol) | 0-24 months | 
| Ultrasound measures of vascularity of the median nerve in the carpal tunnel | Bilateral evaluation of vascularity of the median nerve in the carpal tunnel. Scored 0 to 3 0: no PD signal 1: 1 singular blood vessel 2: 2-3 single blood vessels or 2 confluent 3: ≥4 single blood vessels or ≥ 3 confluent | 0-24 months | 
| Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) | 11-item patient reported outcome measure for disabilities of the arm, shoulder, and hand. (Beaton DE, et al. 2005) | 0-24 months | 
| Patient pain assessment | Patient-reported CTS-related pain on a 0-100 mm visual analogue scale (VAS), where 0 indicates no pain and 100 indicates worst possible pain. | 0-24 months | 
| Work Productivity and Activity Impairment Questionnaire (WPAI) | Patient-reported outcome of physical function in work and activity. (Reilly MC, et al. 1993) | 0-24 months | 
| Days of work absence since start of intervention | Number of days of work absence due to CTS or treatment of CTS since start of intervention | 3-24 months | 
| EuroQoL 5-dimension health-related quality of life (EQ5D-5L) | EuroQoL 5-dimension patient-reported outcome for health-related quality of life. (Herdman M, et al. 2011) | 0-24 months | 
| Adverse events | Number and nature of adverse events and serious adverse events | 0-24 months | 
| Successful treatment after 1 corticosteroid injection | Only applicable in the injection treatment strategy arm. Subjects who have received 1 corticosteroid injection who have attained a successful treatment result (Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5) without surgery | 3-24 months | 
| Successful treatment after 2 corticosteroid injections | Only applicable in the injection treatment strategy arm. Subjects who have received 2 corticosteroid injections who have attained a successful treatment result (Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5) without surgery | 3-24 months | 
| Successful treatment after secondary surgery | Only applicable in the injection treatment strategy arm. Subjects who have received 1 or 2 corticosteroid injections and secondary surgery who have attained a successful treatment result (Boston Carpal Tunnel Questionnaire Symptom Severity Scale ≤ 1.5) | 3-24 months | 
| Undergone re-operation | Subject have received a re-operation (yes/no) A participant who for any reason requires a re-operation, either after primary surgery (surgery arm) or after corticosteroid injection therapy and delayed surgery (injection arm). Reasons for re-operation may, for instance, be wound complications or failure of the initial procedure. NOTE: Secondary (delayed) surgery in a participant in the injection arm in accordance with the study treatment algorithm is not considered a re-operation. | 3-24 months | 
| Cost of treatment | Direct treatment-associated costs, including hospital visits and procedures/interventions. Based on the diagnosis-related group (DRG) pricing system and codified price-lists for medical procedures. | 0-24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Surgery, Corticosteroid injection, Ultrasound guided intervention, Nerve conduction studies, Randomized controlled trial