A Norwegian Trial Comparing Treatment Strategies for Carpal Tunnel Syndrome (NOR-CACTUS)

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.

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.

Surgery, Corticosteroid injection, Ultrasound guided intervention, Nerve conduction studies, Randomized controlled trial

Two-arm, prospective, multi-center, parallel-group, open-label assessor-blinded non-inferiority treatment strategy study

Participants in both strategy arms will have the site for injection/surgery covered with a adhesive bandage prior to assessment by blinded outcome assessors.

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)

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.

Open surgical division of the flexor retinaculum of the palm/wrist to release pressure on the median nerve

Ultrasound-guided injection of 20 mg of triamcinolone hexacetonide (or -acetonide) into the carpal tunnel space close to the median nerve

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.

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.

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.

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.

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.

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.

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

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

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

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

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

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

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

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

Nerve conduction studies of sensory median nerve latency (milliseconds) Median nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance

Nerve conduction studies of sensory median nerve amplitude (microvolts) Median nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance

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

Nerve conduction studies of sensory ulnar nerve latency (milliseconds) Ulnar nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance

Nerve conduction studies of sensory ulnar nerve amplitude (microvolts) Ulnar nerve measurement points: Palmar branch, 8 cm distance, 4th digit with 14 cm distance

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

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

Bilateral test of sensory function in digits 1,2 and 5 using a 2.83 monofilament. Graded absent/present.

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

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).

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).

Patient-reported assessment of CTS-related symptoms (current state), reported on a 5-level ordinal (Likert) scale from 1 (best) to 5 (worst).

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).

Patient assessment if the current CTS-related symptoms and functional disability are acceptable (yes or no)

Bilateral evaluation of the proximal cross-sectional area of the median nerve (square millimeters) (as specified in protocol)

Bilateral evaluation of the distal cross-sectional area of the median nerve (square millimeters) (as specified in protocol)

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

11-item patient reported outcome measure for disabilities of the arm, shoulder, and hand. (Beaton DE, et al. 2005)

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.

EuroQoL 5-dimension patient-reported outcome for health-related quality of life. (Herdman M, et al. 2011)

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

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

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)

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.

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.

Use of primary care resources based on data from Norwegian municipal patient- and user register (KPR)

Work participation based on data from Statistics Norways's (SSB) event database for social services (FD Trygd)

Unit costs will be assigned to each type of service by means of the diagnosis-related group (DRG) pricing system, and the price list of the Norwegian Medicines Agency. For each patient total costs will be estimated utilization of health care and social services. The mean symptom severity and cost in the two treatment arms will be used to estimate a cost-effectiveness ratio for the treatment strategies.

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

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