Trial document




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  DRKS00004161

Trial Description

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Title

Total versus near-total thyroidectomy in Graves`disease- a multi centered prospective randomized controlled clinical trial to evaluate postoperative transient hypoparathyroidism after definite surgery in Graves`disease

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Trial Acronym

TONIG

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Our purpose is to enhance quality of life in patients who have to undergo surgery for the definite therapy of hyperthyroidism in Graves` disease.
Graves`disease is a so called autoimmune disease where the immune system reacts against the thyroid gland. The process causes a stimulation of the thyroid gland leading to a hyper function called hyperthyroidism. In case hyperthyroidism cannot be controlled by a certain medication any longer for severity or recurrence, the thyroid function can be turned off through a radioactive ablation via the blood stream through an injection of radioactive iodine called radio iodine therapy. If this is not possible in rather large glands, for medical reasons such as pregnancy, desired pregnancy or because the patient disagrees, the only way to treat hyper function is the removal of the thyroid gland by surgery. After radio iodine therapy or surgery, life long thyroid hormone medication is necessary.
The autoimmune reaction causes inflammatory processes in he thyroid tissue. The tissue is very well vascularized and far more vulnerable . The tissue changes therefore complicate the operation.
Every kind of thyroid surgery requires a thorough protection of the parathyroid glands. These are normally four tiny glands on both sides of the thyroid located behind the upper and lower edge of the gland. The parathyroid glands are separate small organs with a size comparable to a lentil. They control the calcium level in the blood. A defined constant level is necessary to maintain a popper function of nerves and muscles. To guarantee an adequate calcium level at least one sound gland is necessary. Due to their small size, the location and the above describes tissue changes in Graves`disease, the parathyroid glands are especially at risk during thyroid surgery for Graves`disease. Therefore a temporary hypo function of the parythroids up to six months after surgery is common. The hypo function of the parathyroid gland causes dysfunctioning of muscles and nerves, may cause depression and reduces activity and quality of life. A constant medication is necessary to avoid these changes and the therapy has to be monitored thoroughly through regular blood examinations. In the past the paraythroid function after surgery in Graves`disease has been already examined. Yet all trials mainly focussed on the recurrence of the hyper function after partial or either total removal of the gland. There is strong evidence that an innovative operation technique -where instead of the removal of the whole thyroid gland small thyroid remnants of 1 g are spared on each side- may reduce the risk of hypo functioning parathyroid glands without an enhanced risk for recurrence of Graves`disease. Patients with Graves`disease who need surgery for the definite therapy of thyroid hyper function are able to take part in the present trial. The patient will be allocated to either the so called intervention group or the control group by hazard. In the so called intervention group small remnants of thyroid tissue (1g or less than 1 g) will be spared on each side, while in the control group the whole thyroid will be taken out. Both techniques are known and well-established surgical principles. There are no additional risks for the patient than the general risks of thyroid surgery he or she is informed about by his or her surgeon. The risk of recurrent hyper function of the remaining small thyroid remnants is extremely unlikely according to the best of our knowledge. But in any case a recurrent hyper function will be detected immideately because the patient will be under constant supervision and follow-up. Is a medical treatment of recurrent hyper function of the thyroid remnants not possible for any reason, the small remnants may be easily controlled by a radioactive ablation with radioactive marked iodine. Only if this again is not possible for medical or personal reasons a re-operation might be necessary. The risk to undergo re-operation however is estimated to be zero percent according to the best of our knowledge.
After surgery, there will be a regular follow up for the measurement of calcium and paraythroid and thyroid hormone levels in the blood. before and after surgery patients` vocal cords will be checked to ensure that surgery did not cause any harm to the nerve controlling the function of the vocal cords. Before and 6 weeks after surgery the patient will be asked to answer questions assessing quality of live.
In case endocrine orbiotopathy can be assumed according to the medical history or the clinical aspect before or 12 months after surgery, an ophthalmologist will check for any changes that may occur in Graves`disease. In summary the trial serves to test assumption that hypo function of the parathyroids after surgery for Graves`disease can be significantly reduces through the innovated operation technique. Moreover general risks of thyroid surgery will be checked such as bleeding, or impairment of vocal cord function.

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Brief Summary in Scientific Language

Background:
Graves`disease is an independent risk factor for transient postoperative hypoparythyroidism. Besides the disease itself, preparation techniques are influential. Transient postoperative hypoparathyrsoidism has severe consequences for patients physically and psychologial state. It can be life threatening during the acute phase and impairs patients` health, psyche and qality of life thereafter. For the surgical therapy of Graves` disease, total thyroidectomy is recommanded accordig to the national guideline. The evidence- based on a metanalysis- is critizised by the Cochrane diagnostic review commentary for substantial methodological deficits. Two randomized controlled trials lead to the hypothesis that a near-total ressection with bilateral remnants of ≤ 1g on each side compared to total thyroidectomy will significantly reduce the occurence of transient postoperative hypoparthyrsoidism with eaqual safety.

Methods/Design:
Patients with Graves`disease indicated for definite surgery are eligble for the trial. Trial-specific exclusion criteria are: conservative treatment, malignancy, previous thyroid surgery and coincident hypoerparathyrsoidism. The trial is created for therpeutic purpose through process inovation. It is designed as a prospective randomized controlled patient and observer blinded multicentered trial in a parallel design including an active comperator and intervention group. The intervention adresses the surgical procedure: near-total thyroidectomy leaving bilateral remnants of ≤ 1g on each side in the intervention group and total thyroidectomy in the controle group. Occurrence of transient postoperativ hypoparythroisdism is defined as primary endpoint. Secondary endpoints are: reoperations due to bleeding, reccurent laryngeal nerve palsy, permanent hypoparythsroidism, recurrent disease, changes of endocrine orbitopathy and quality of life within a one-year follow up period. The primary efficacy analysis follows the intention-to-treat principle. A binary logistic regression model will be applied. Complications and seroius adverse events will be descriptively analysed.

Discussion:
The trial is expected to balance out the shortcommigs of the current evidence. It will define the surgical goldstandard of the ressection principle in Graves` disease. Patients safety and quality of life are assumed to be enhanced, therapy costs reduced and health care optimized. The conduction of the trial is feasible through the engagement and committment of the German association of endocrine surgeons and the National Network for Surgical Trials.

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Organizational Data

  •   DRKS00004161
  •   2012/06/04
  •   [---]*
  •   yes
  •   Approved
  •   53/12, Ethik-Kommission des Fachbereichs Medizin der Philipps-Universität Marburg
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   E89.2 -  Postprocedural hypoparathyroidism
  •   E05.0 -  Thyrotoxicosis with diffuse goitre
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Interventions/Observational Groups

  •   Near-totoal thyroidectomy (near-tital removal of the thyroid gland leaving bilateral remnants of </= 1g on each side around the lateral thyrohyoid ligament of Berry)
  •   Total thyroidectomy (total removal of the thyroid gland)
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Blinded
  •   patient/subject
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

The incidence of transient hypoparathyroidism is defined as the primary efficacy endpoint. Transient hypoparathyroidism is defined as an inadequate parathyroid function not exceeding six months after surgery. Serum calcium- and parathyroid hormone- (PTH) levels and substitutional medication to achieve normocalcemia are used to assess hypoparathyroidism. No evidenece- or consensus based definition of postoperative hypoparathyroidism based on calcium and PTH cut-off levels exists. Therefore, we defined postoperative hypoparathyroidism as calcium and PTH levels below the normal range. Postoperative hypoparathyroidism is considered to be symptomatic in case of at least one of the following symptoms: carpo-pedal paresthesia, numbness or spams and anxiety. Application type, form and dosage of calcium and vitamin-D substitution therapy to achieve normocalcemia are registered. Postoperative hypoparathyroidism is defined transient, if calcium and vitamin-D substitution therapy to achieve normocalcemia are required for less than six months after surgery. The parameters are recorded before surgery, at the day of discharge, six months and 12 months after surgery.

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Secondary Outcome

Secondary outcome measures comprise the incidences of permanent hypoparathyroidism, recurrent Graves’ disease, temporary and permanent recurrent laryngeal nerve palsy and reoperations due to bleeding and the number of inadvertently removed parathyroids as well as changes of endocrine orbitopathies and quality of life.
Permanent hypoparythroidism is defined as persisting inadequate parathyroid function exceeding six months after surgery. The incidence of recurrent Graves’ disease is assessed through laboratory thyroid function tests (TSH < 0.34 U/l, fT3 > 6.5 pmol/l, fT4 > 21 pmol/l) and the antibody level of thyroidea receptor anti-body (TRAK > 1.75U/l) six weeks, six months and 12 months after surgery with respect to concomitant substitution or thyreostatic medications to achieve an euthyroid state. Cervical ultrasound follows elevated antibody levels to screen for recurrence. Reoperations are reported as serious adverse events. Incidences of temporary and permanent recurrent laryngeal nerve palsies are assessed through laryngoscopy on the day of discharge and, in case of pathological findings within this examination only, at the six weeks, six months and 12 months after surgery. The number of inadvertently removed parathyroids will be counted from histopathology reports at the day of discharge. In case endocrine orbitopathy can be assumed from medical history and/or clinical examination before and/or 12 months after surgery, an ophthalmologist will check for chracteristics of endocrine orbitopathy . Changes in Quality of life are scored before surgery and 6 weeks thereafter using the validated multipurpose health survey questionnaire SF36.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
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Recruitment

  •   Actual
  •   2015/09/01
  •   300
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

Patients with Graves` disease indicated for definite surgery according to the national guideline; indications are: intolerance of thermostatic medication, persistent or recurrent hyperthyreosis, thyroid growth, endocrine orbitopathy, contraindications for radio iodine therapy; other inclusion criteria are: no history of previous thyroid- and/ or parathyroid surgery; Normal vocal cord function; Age >/= 18 years; Expectancy of life greater than 12 months; Informed consent

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Exclusion Criteria

Patients with Graves` disease eligible for conservative treatment; (Suspected) malignancy; impairment of parathyroid function; Neurophysiological deficiencies

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Addresses

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    • Klinik für Viszeral-, Thorax- und Gefäßchirurgie Universitätsklinikum Gießen und Marburg GmbH- Standort Marburg
    • Mr.  Universotätsprofessor Prof. Dr. med.  Detlef Klaus  Bartsch 
    • Baldingerstraße
    • 35043  Marburg
    • Germany
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    • Koordinierungszentrum für klinische Studien- KKS Philipps-Universität Marburg
    • Mr.  Maik  Hahmann 
    • Karl-von-Frisch-Straße 4
    • 35043  Marburg
    • Germany
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    • Koordinierungszentrum klinische Studien- KKS Philipps- Univeristät Marburg
    • Ms.  Carmen  Schade-Brittinger 
    • Karl-von-Frisch Straße 4
    • 35043  Marburg
    • Germany
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    • Klinik für Viszeral-, Thorax- und Gefäßchirurgie Universitätsklinikum Gießen und Marburg GmbH- Standort Marburg
    • Ms.  Dr. med.  Katja  Maschuw 
    • Baldingerstraße
    • 35043  Marburg
    • Germany
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    • Klinik für Viszeral-, Thorax- und Gefäßchirurgie Universitätsklinikum Gießen und Marburg GmbH- Standort Marburg
    • Ms.  Dr. med.  Katja  Maschuw 
    • Baldingerstraße
    • 35043  Marburg
    • Germany
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Sources of Monetary or Material Support

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    • Medical Board Röhn Klinikum AGFörderpool 2015/2016
    • Rudolf-Buchheim-Str. 8
    • 35385  Gießen
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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